Vagal nerve stimulation therapy

ABSTRACT

Devices, systems and methods are provided for treating post-operative symptoms following major surgery and/or for treating patients in critical or intensive care. A method includes positioning a contact surface of a device in contact with an outer skin surface of patient and applying an electrical impulse transcutaneously from the device through the outer skin surface of the patient to a vagus nerve in the patient for about 60 seconds to about 5 minutes. The electrical impulse is sufficient to modify the vagus nerve such that the symptoms are reduced. A stimulation protocol is provided that includes two or more doses administered per day for a period of time sufficient to relieve the symptoms. The doses may be administered before and after the patient&#39;s surgery, or while the patient is being treating in intensive care.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a Continuation-In-Part of U.S. Nonprovisionalapplication Ser. No. 16/838,953, filed Apr. 2, 2020, which is aContinuation-in-Part of U.S. Nonprovisional application Ser. No.16/229,299 filed 21 Dec. 2018; which claims the benefit of U.S.Provisional Application No. 62/609,807 filed 22 Dec. 2017; all of whichare hereby incorporated by reference for all purposes as if copied andpasted herein.

This patent application is also related to the followingcommonly-assigned patents and patent applications: U.S. Nonprovisionalapplication Ser. No. 14/335,726 filed 18 Jul. 2014, U.S. Nonprovisionalapplication Ser. No. 14/292,491 filed 30 May 2014, now U.S. Pat. No.9,375,571 issued 28 Jun. 2016, U.S. Nonprovisional application Ser. No.13/858,114 filed 8 Apr. 2013, now U.S. Pat. No. 9,248,286 issued 2 Feb.2016, U.S. Nonprovisional application Ser. No. 14/930,490 filed 2 Nov.2015, U.S. Nonprovisional application Ser. No. 13/222,087 filed 31 Aug.2011, now U.S. Pat. No. 9,174,066 issued 3 Nov. 2015, U.S.Nonprovisional application Ser. No. 13/183,765 filed 15 Jul. 2011, nowU.S. Pat. No. 8,874,227 issued 28 Oct. 2014, U.S. Nonprovisionalapplication Ser. No. 13/183,721 filed 15 Jul. 2011, now U.S. Pat. No.8,676,324 issued 18 Mar. 2014, U.S. Nonprovisional application Ser. No.13/109,250 filed 17 May 2011, now U.S. Pat. No. 8,676,330 issued 18 Mar.2014, U.S. Nonprovisional application Ser. No. 13/075,746 filed 30 Mar.2011, now U.S. Pat. No. 8,874,205 issued 28 Oct. 2014, U.S.Nonprovisional application Ser. No. 13/005,005 filed 12 Jan. 2011, nowU.S. Pat. No. 8,868,177 issued 21 Oct. 2014, U.S. Nonprovisionalapplication Ser. No. 12/964,050 filed 9 Dec. 2010, U.S. Nonprovisionalapplication Ser. No. 12/859,568 filed 19 Aug. 2010, now U.S. Pat. No.9,037,247 issued 19 May 2015, U.S. Nonprovisional application Ser. No.12/612,177 filed 4 Nov. 2009, now U.S. Pat. No. 8,041,428 issued 18 Oct.2011, U.S. Nonprovisional application Ser. No. 12/408,131 filed 20 Mar.2009, now U.S. Pat. No. 8,812,112 issued 19 Aug. 2014, U.S.Nonprovisional application Ser. No. 15/149,406 filed 9 May 2016, U.S.Nonprovisional application Ser. No. 14/337,930 filed 22 Jul. 2014, nowU.S. Pat. No. 9,333,347 issued 10 May 2016, U.S. Nonprovisionalapplication Ser. No. 13/075,746 filed 30 Mar. 2011, now U.S. Pat. No.8,874,205 issued 28 Oct. 2014, U.S. Nonprovisional application Ser. No.12/964,050 filed 9 Dec. 2010, U.S. Nonprovisional application Ser. No.12/859,568 filed 19 Aug. 2010, now U.S. Pat. No. 9,037,247 issued 19 May2015, U.S. Nonprovisional application Ser. No. 14/462,605 filed 19 Aug.2014, U.S. Nonprovisional application Ser. No. 13/005,005 filed 12 Jan.2011, now U.S. Pat. No. 8,868,177 issued 21 Oct. 2014, U.S.Nonprovisional application Ser. No. 12/964,050 filed 9 Dec. 2010, U.S.Nonprovisional application Ser. No. 12/859,568 filed 19 Aug. 2010 nowU.S. Pat. No. 9,037,247 issued 19 May 2015 and U.S. Nonprovisionalapplication Ser. No. 12/408,131 filed 20 Mar. 2009 now U.S. Pat. No.8,812,112 issued 19 Aug. 2014; all of which are hereby incorporated byreference for all purposes as if copied and pasted herein.

BACKGROUND

The field of the present invention generally relates to the delivery ofelectrical impulses (and/or fields) to bodily tissues for therapeuticpurposes, and more specifically to vagal nerve stimulation devices andmethods for treating patient's suffering from post-operative symptomsfollowing major surgery and/or for treating patients in critical orintensive care, such as those patient's suffering from symptoms ofstroke, transient ischemic attack (TIA), heart, kidney or respiratoryfailure, shock, sepsis, severe burns, severe illnesses (e.g., COVID-19)and the like.

The use of electrical stimulation for treatment of medical conditions iswell known. For example, electrical stimulation of the brain withimplanted electrodes (deep brain stimulation) has been approved for usein the treatment of various conditions, including pain and movementdisorders such as essential tremor and Parkinson's disease [Joel S.PERLMUTTER and Jonathan W. Mink. Deep brain stimulation. Annu. Rev.Neurosci 29 (2006):229-257].

Another application of electrical stimulation of nerves is the treatmentof radiating pain in the lower extremities by stimulating the sacralnerve roots at the bottom of the spinal cord [Paul F. WHITE, Shitong Liand Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic PainManagement. Anesth Analg 92(2001):505-513; patent U.S. Pat. No.6,871,099, entitled Fully implantable microstimulator for spinal cordstimulation as a therapy for chronic pain, to WHITEHURST, et al].

The type of electrical stimulation that is most relevant to the presentdisclosure is vagus nerve stimulation (VNS, also known as vagal nervestimulation). It was developed initially for the treatment of partialonset epilepsy and was subsequently developed for the treatment ofdepression and other disorders. The left vagus nerve is ordinarilystimulated at a location within the neck by first implanting anelectrode about the vagus nerve during open neck surgery and by thenconnecting the electrode to an electrical stimulator circuit (a pulsegenerator). The pulse generator is ordinarily implanted subcutaneouslywithin a pocket that is created at some distance from the electrode,which is usually in the left infraclavicular region of the chest. A leadis then tunneled subcutaneously to connect the electrode assembly andpulse generator. The patient's stimulation protocol is then programmedusing a device (a programmer) that communicates with the pulsegenerator, with the objective of selecting electrical stimulationparameters that best treat the patient's condition, e.g., pulsefrequency, stimulation amplitude, pulse width, etc.

The body typically becomes stressed by the effects of anesthesia andsurgery. The amount of discomfort or other symptoms following surgerydepends on many factors, including the type of surgery performed.Typical discomforts include nausea and vomiting from general anesthesia,exhaustion, sore throat, soreness, post-operative pain, restlessness,sleeplessness, thirst, constipation, gas and post-operative ileus.

Post-operative ileus (POI) may be defined as the impairment ofgastrointestinal (GI) motility after intra-abdominal or nonabdominalsurgery. It is characterized by bowel distention, lack of bowel sounds,accumulation of GI gas and fluid, and delayed passage of flatus andstool. POI occurs in 10%-20% of patients undergoing elective colorectalsurgery. A higher incidence is associated with abdominal and pelvicsurgery, open laparotomy, longer surgery time, greater estimated bloodloss, prolonged opioid use, and inhalational anesthesia. Risk factorsfor POI include type of surgery and preexisting factors such as GIdisease and physical inactivity.

POI affects all segments of the GI tract. It usually is uncomplicatedand resolves spontaneously within 2 to 3 days, although it may last 6days or more. The return of bowel function is commonly identified byactive bowel sounds, the passage of flatus, and/or a bowel movement. Themost reliable markers of bowel-function return are having a bowelmovement and being able to tolerate oral intake. An ileus that lastsmore than 3 days is considered a paralytic, or adynamic, ileus

For patients, POI prolongs the length of hospital stay and increases therisk of serious complications such as pneumonia and venousthromboembolic events. For healthcare systems, it increases costs by upto 71%, particularly those associated with nursing care, laboratoryinvestigations and medications.

The mechanism of ileus is multifactorial, with most evidence pointingtowards opioid- and inflammatory-induced dysfunction of intestinaltransit. POI may result from the use of postsurgical opioid painrelievers (e.g., morphine), which can slow or inhibit normal motility.Opioid analgesics relieve pain by blocking pain signals throughstimulation of opioid receptors (mu receptors) located on the surface ofthe nerves that transmit these signals. Opioid analgesics bind to the mureceptors in the central nervous system (CNS) and the GI tract. Thebinding of opioid analgesics to mu receptors in the GI tract greatlyslows intestinal motility, thereby disrupting normal GI function. Theslowing of intestinal motility may cause significant discomfort andpain. The combination of both endogenous and exogenous opioids maycontribute to the development and persistence of ileus. Increased dosesof opioid analgesics are related to extended periods of POI.

The effects of anesthesia and antispasmodics on the colon may also causePOI. The large intestine is devoid of intercellular gap junctions, whichmakes the colon more susceptible to the inhibitory actions ofanesthetics. In particular, halothane, enflurane, and atropine delaygastric emptying. Some studies have shown that thoracic epidurals withbupivacaine hydrochloride significantly reduce ileus versus systemicopioid therapy in patients undergoing abdominal surgical procedures.Epidurals with local anesthetics are believed to block inhibitoryreflexes and have other beneficial effects.

Paralytic ileus may also result from intraperitoneal or retroperitonealinflammation (e.g., appendicitis, diverticulitis, perforated duodenalulcer); retroperitoneal or intra-abdominal hematoma (e.g., rupturedabdominal aortic aneurysm, lumbar compression fracture); metabolicdisturbances (e.g., hypokalemia); or medications (e.g., opioids,anticholinergics, calcium channel blockers, anesthetics). Ileussometimes occurs in association with renal or thoracic disease (e.g.,lower lobe pneumonitis, lower rib fracture, myocardial infarction).

In the last 20 years, a number of interventions to prevent ileus and itssequelae have been explored, but few have led to meaningful patientbenefit. The most promising have included strategies to rationalizeopioid-based analgesia (such as mu-receptor antagonists) and to moderatethe postoperative inflammatory response, such as enhanced recoveryprotocols.

Patients are treated critical or intensive care for a variety of causes,such as stroke, transient ischemic attack (TIA), heart, kidney orrespiratory failure, shock, sepsis, severe burns, severe illnesses(e.g., COVID-19) and the like. A stroke is the acute loss of brainfunction due to loss of normal blood supply to the brain or brainstem,spinal cord, or retina. This can be due to the lack of blood flow(ischemia) caused by blockage of a blood vessel due to thrombosis orarterial embolism. Stroke may also be due to a hemorrhage. A thromboticstroke occurs when a blood clot (thrombus) forms in one of the brain'sarteries, which may be formed in the vicinity of fatty deposits (plaque)that build up in the artery to cause reduced blood flow(atherosclerosis). Less commonly, the thrombus may form at the site of avasospasm of a migraine sufferer. A thrombus can block a large brainartery (causing widespread brain damage) or a small artery, the latterresulting in a so-called lacunar stroke. An embolic stroke occurs when ablood clot or other debris (embolus) forms outside brain, for example inan atrium of the patient's heart, and is transported through thebloodstream to lodge in an artery of the brain. About half to two-thirdsof all strokes are thrombotic strokes.

Ischemic stroke occurs in 87% of stroke patients and may be eithersymptomatic or silent. Symptomatic ischemic strokes are manifest byclinical signs of focal or global cerebral, spinal, or retinaldysfunction caused by death of neural tissue (central nervous systeminfarction). A silent stroke is a documented central nervous systeminfarction (tissue death due to lack of oxygen) that was asymptomatic.Symptomatic ischemic strokes are usually treated with thrombolyticagents (“clot busters”), preferably within three hours of the onset ofthe stroke. In contrast, hemorrhagic strokes occur in 13% of strokepatients, who may be treated by neurosurgery. Hemorrhagic strokesinclude bleeding within the brain (intracerebral hemorrhage) andbleeding between the inner and outer layers of the tissue covering thebrain (subarachnoid hemorrhage).

A stroke causes an infarct, which comprises irreversibly dead or dyingneuronal tissue that has been deprived of oxygen. The infarct issurrounded by a penumbra of ischemic tissue, which is salvageable withprompt restoration of oxygen through blood perfusion. Therefore, promptdiagnosis and treatment of the stroke patient is essential in order tosave as much of the penumbra tissue as possible, thereby saving theneuronal functions that are performed by that salvageable tissue.Ischemic stroke is generally painless, and the patient usually remainsconscious during the diagnosis. Neurological symptoms that are exhibitedby the patient upon interrogation and examination are used to make apreliminary evaluation as to whether a stroke has occurred.

A transient ischemic attack (TIA) is also caused by ischemia in thebrain, spinal cord or retina. TIAs share the same underlying etiology asischemic strokes and produce the same symptoms, such as contralateralparalysis, sudden weakness or numbness, dimming or loss of vision,aphasia, slurred speech and mental confusion. Unlike a stroke, thesymptoms of a TIA can resolve typically within a day, whereas thesymptoms from a stroke can persist due to death of neural tissue (acuteinfarction). Thus, a transient ischemic attack may be defined as atransient episode of neurological dysfunction caused by focal brain,spinal cord, or retinal ischemia, without acute infarction [EASTON J D,Saver J L, Albers G W, et al. Definition and evaluation of transientischemic attack: a scientific statement for healthcare professionalsfrom the American Heart Association/American Stroke Association StrokeCouncil et al. Stroke 40(6, 2009):2276-2293; PRABHAKARAN S. Reversiblebrain ischemia: lessons from transient ischemic attack. Curr Opin Neurol20(1, 2007):65-70].

Stroke accounts for approximately 9.7% of all deaths worldwide. It isthe third-leading cause of death in the United States, with more than140,000 people dying of stroke each year. Some 795,000 individualssuffer a stroke annually in the U.S. (269 per 100,000 population), with600,000 of these strokes representing first-time attacks. Stroke alsocauses a substantial medical burden for those individuals who survive astroke. Overall case-fatality within 1 month of stroke onset is about23%, but is higher for intracerebral hemorrhage (42%) and subarachnoidhemorrhage (32%) than for ischemic stroke (16%). Among all nonpediatricpopulations, stroke is the fourth-leading cause of lostdisability-adjusted life-years, behind only to HIV/AIDS, unipolardepressive disorders, and ischemic heart disease. The total cost ofstroke to the United States is estimated at $43 billion per year,consisting of direct costs of medical care and therapy at $28 billionper year and indirect costs from lost productivity and other factors at$15 million per year [Debraj MUKHERJEE and Chirag G. Patil. Epidemiologyand the Global Burden of Stroke. World Neurosurg 76(6 Suppl,2011):S85-S90; FEIGIN V L, Lawes C M, Bennett D A, Anderson C S. Strokeepidemiology: a review of population-based studies of incidence,prevalence, and case-fatality in the late 20th century. Lancet Neurol2(1, 2003):43-53].

The estimated annual number of TIAs in the U.S. is about 200 to 500thousand, although the number is difficult to estimate because TIAs maybe under-reported, considering that they typically last less than anhour. It is not well known by the general public that a TIA is a medicalemergency requiring prompt medical attention. Approximately 10% ofstrokes are preceded by one or more TIAs. An estimated one-third of allTIAs are followed by a stroke within five years [JOHNSTON S C. Transientischemic attack. N Engl J Med. 347(2002):1687-1692].

Intravenous fibrinolytic (clot dissolving) therapy for acute stroke iscurrently the primary treatment for ischemic stroke, using intravenousrecombinant tissue plasminogen activator (rtPA) at 0.9 mg/kg with amaximum dose of 90 mg, over 60 minutes, with 10% of the dose given as abolus over 1 minute. The major risk of intravenous rtPA treatment issymptomatic intracranial hemorrhage (sICH). The fibrinolytic therapy ispreferably initiated within three hours of the stroke onset, and withinone hour after arrival in the emergency room, but the therapy may beuseful at up to 4.5 hours after onset of the stroke.

If intravenous fibrinolytic treatment is contraindicated in a patient,or if it does not produce the desired results, other treatment optionsare available. Endovascular treatment of ischemic stroke has increasedsubstantially over the past decade to include: (1) intra-arterialfibrinolysis, possibly in conjunction with intravenous fibrinolysis; (2)mechanical clot retrieval through mechanical embolectomy usingmicro-guidewires, micro-snares, retrievers and aspirators, such as theMERCI L5 device (Concentric Medical, Inc, Mountain View, Calif.) and thePenumbra System (Penumbra, Inc, Alameda, Calif.); and (3) acuteangioplasty and stenting, e.g., using the TREVO Retriever (ConcentricMedical, Inc, Mountain View, Calif.).

The use of thrombin inhibitors and certain anticoagulation therapy(heparin and the like) is not currently recommended. However, oraladministration of the antiplatelet agent aspirin (initial dose is 325mg) within 24 to 48 hours after stroke onset is recommended fortreatment of most patients.

Neuroprotective treatment of a stroke patient may also be attempted.Neuroprotection refers to using a therapy that directly affects thebrain tissue to salvage or delay the infarction of the still-viableischemic penumbra, rather than reperfusing the tissue. Neuroprotectivestrategies include antagonizing the effects of excitatory amino acids,such as glutamate, transmembrane fluxes of calcium, intracellularactivation of proteases, apoptosis, free radical damage, inflammation,and membrane damage. More than a thousand neuroprotective therapies havebeen proposed [O'COLLINS V E, Macleod M R, Donnan G A, Horky L L, vander Worp B H, Howells D W. 1,026 Experimental treatments in acutestroke. Ann Neurol 59(2006):467-477; GINSBERG M D. Neuroprotection forischemic stroke: past, present and future. Neuropharmacology55(2008):363-389; KIDWELL C S, Liebeskind D S, Starkman S, Saver J L.Trends in acute ischemic stroke trials through the 20th century. Stroke32 (2001):1349-1359]. These include the use of drugs that limit thecellular effects of acute ischemia or reperfusion (nimodipine,lubeluzole, clomethiazole, NXY-059, tirilazad, citicoline, enlimomab,cerebrolysin, statins, erythropoietin, magnesium, and even thecombination of caffeine and alcohol) [PIRIYAWAT P, Labiche L A, Burgin WS, Aronowski J A, Grotta J C. Pilot dose-escalation study of caffeineplus ethanol (caffeinol) in acute ischemic stroke. Stroke34(2003):1242-1245].

Another treatment is the use of hypothermia, which has been shown to beneuroprotective in experimental and focal hypoxic brain injury models.An older neuroprotective strategy is the use of hyperbaric oxygen, butclinical data concerning its use are inconclusive, and some data implythat the intervention may be harmful. A relatively new neuroprotectivetreatment is the application of a near-infrared laser light to theshaved skull to selectively deliver energy to mitochondria in thedamaged region [YIP S, Zivin J. Laser therapy in acute stroke treatment.Int J Stroke 3(2008):88-91].

What is needed, therefore, are improved systems and methods for treatingpatient's suffering from post-operative symptoms following majorsurgery, such as POI, and improved systems and methods for treatingpatients in critical or intensive care, such as those patient'ssuffering from symptoms of stroke, transient ischemic attack (TIA),heart, kidney or respiratory failure, shock, sepsis, severe burns,severe illnesses (e.g., COVID-19) and the like.

SUMMARY

This disclosure relates generally to the delivery of electrical impulsesto bodily tissues for therapeutic purposes, and more specifically tovagal nerve stimulation devices for treating patient's suffering frompost-operative symptoms following major surgery and/or for treatingpatients in critical or intensive care. Post-operative symptoms mayinclude nausea, vomiting, constipation, gas, post-operative ileus,post-operative pain, restlessness, sleeplessness and the like. In someembodiments, the systems and methods of the present disclosure areparticularly useful for mitigating or eliminating the impairment ofgastrointestinal (GI) motility after intra-abdominal or nonabdominalsurgery, such as post-operative ileus (POI). In some embodiments, thesystems and methods may reduce opioid-induced and/orinflammatory-induced dysfunction of intestinal transit to improvemotility, thereby allowing faster release of patient's from thehospital.

Critical or intensive care is the specialized care of patients whoseconditions are life-threatening and who require comprehensive care andconstant monitoring, usually in intensive care units. Such conditionsmay include stroke, transient ischemic attack (TIA), heart, liver,kidney or respiratory failure, shock, heart attack, sepsis, severeburns, severe bleeding, severe illnesses (e.g., COVID-19) and the like.In some embodiments, the systems and methods of the present disclosuremay be used to treat various symptoms of these conditions.

In one aspect, a method comprises positioning a contact surface of adevice in contact with an outer skin surface of a patient. An electricalimpulse is applied transcutaneously from the device through the outerskin surface of the patient to a vagus nerve in the patient according toa stimulation protocol. The stimulation protocol includes at least twodoses administered each day for a plurality of days until thepost-operative symptoms are reduced. The doses each have a duration ofabout 60 seconds to about 5 minutes, preferably about 90 seconds to 3minutes.

In some embodiments, the doses are administered immediately followingthe patient's surgery for about 2 to about 5 days thereafter or untilsymptoms have improved. In other embodiments, the doses may beadministered prior to surgery (e.g., 2 to 5 days prior to surgery) as analternative, or in addition to, the doses administered followingsurgery. Applicant has discovered that, in some instances, prophylactictreatment of patients with vagal nerve stimulation prior to the insultcaused by the surgery improves outcomes.

The device may comprise one or more electrodes that are adhered, orotherwise attached to, the outer skin surface of a neck of the patient.This allows the patient to be treated without direct intervention (i.e.,holding a device or the electrodes against the patient's neck duringstimulation). The system may further comprise an outer sheath or otherwearable device, such as a insulating strip, a collar, or a garment,such as a turtleneck, a scarf or the like, that functions to adhere theelectrodes to the neck of the patient. The electrodes may be housedwithin the wearable device, or positioned between the wearable deviceand the neck of the patient.

In some embodiments, the electrodes are coupled to a source via one ormore leads such that the electrical impulse is transmitted to theelectrodes from an energy source through the leads. In otherembodiments, the method further comprises wirelessly transmitting theelectrical impulse to the one or more electrodes. In yet anotherembodiment, the electrodes are part of a housing, such as a handhelddevice, that contains the energy source.

In an alternative embodiment, the device comprises a patch that includesat least one adhesive surface for attachment to the outer skin surfaceof the neck of the patient. The electrodes are housed within the patch.The patch may further comprise a signal generator and an energy sourcefor applying the electrical impulses through the electrodes to the vagusnerve. Alternatively, the patch may include a wireless receiver andassociated electronics for wirelessly receiving the electrical impulseand/or the energy from the energy source.

In certain embodiments, the doses are separated by a time frame of aboutfive to 15 minutes. In other embodiments, the method comprisesadministered two doses consecutively and then continuing to administertwo doses multiple times/day. In still other embodiments, the doses maybe separated by at least one hour, or between about four to about 12hours. The stimulation protocol may comprise 2 to 12 treatments/day,preferably between about 2 to 4 treatments.

In certain embodiments, the electrical impulse comprises pulses having afrequency of about 1 kHz to about 20 kHz. The electrical impulse maycomprise bursts of pulses, with each burst having a frequency of about 1to about 100 bursts per second and each pulse has a duration of about 50to about 1000 microseconds in duration. The bursts each comprise about 2to 20 pulses and the bursts are separated by an inter-burst period thatcomprises zero pulses.

In certain embodiments, the electrical impulse is sufficient to reduceintraperitoneal or retroperitoneal inflammation. The electrical impulsemay be sufficient to suppress inflammatory cytokine levels viaactivation of the Cholinergic Anti-inflammatory Pathway (CAP). The CAPis believed to be the efferent vagus nerve-based arm of the inflammatoryreflex, mediated through vagal efferent fibers that synapse onto entericneurons, which release acetylcholine (Ach) at the synaptic junction withmacrophages. Stimulation of the CAP leads to Ach binding toα-7-nicotinic ACh receptors (α7nAChR), resulting in reduced productionof the inflammatory cytokines TNF-a, IL-1b, and IL-6, but not theanti-inflammatory cytokine, IL-10.

In other embodiments, the electrical impulse is sufficient to directlyinhibit a release of a pro-inflammatory cytokine, such as necrosisfactor (TNF)-alpha and IL-1β. These cytokines are typically elevated incertain patients suffering from symptoms of critical conditions.

In other embodiments, the electrical impulse is sufficient to increasethe anti-inflammatory competence of certain cytokines to thereby offsetor reduce the effect of pro-inflammatory cytokines.

In other embodiments, the electrical impulse is sufficient to reducepost-operative pain. Reduction of post-operative pain may reduce thepatient's reliance on postsurgical opioid pain relievers (e.g.,morphine), which can slow or inhibit normal motility. This, in turn, mayincrease motility and/or reduce the symptoms of POI in the patient,thereby allowing faster release of the patient from the hospitalfollowing surgery.

In another aspect, a device for treating post-operative symptoms in apatient comprises one or more electrodes configured for contacting anouter skin surface of the patient. An energy source is coupled to theelectrodes. The energy source is configured to generate at least oneelectrical impulse and to transmit the at least one electrical impulsetranscutaneously from the electrodes through the outer skin surface ofthe patient to a vagus nerve in the patient according to a stimulationprotocol. The stimulation protocol includes at least two 90 second totwo minute doses administered each day for a plurality of days.

In certain embodiments, the one or more electrodes are configured forattachment to the outer skin surface of the neck of the patient suchthat the stimulation protocol may be administered to the patient withoutself-treatment. This allows for treatment to occur even when the patientis unable or unwilling to comply with the treatment regimen. The energysource may be wirelessly coupled to the one or more electrodes.Alternatively, the device further comprises one or more electricalconnectors or lead wires coupling the energy source to the one or moreelectrodes.

In other embodiments, the device further comprises a housing, such as ahandheld device, that may be operated by the patient. The energy sourceis housed within the housing and the electrodes are attached to, orincorporated into, the housing.

In other embodiments, the device comprises a patch having at least oneadhesive surface for attachment to the outer skin surface of the neck ofthe patient. The electrodes are housed within the patch. The patch mayfurther comprise a signal generator and an energy source for applyingthe electrical impulses through the electrodes to the vagus nerve.Alternatively, the patch may include a wireless receiver and associatedelectronics for wirelessly receiving the electrical impulse and/or theenergy from the energy source.

The device may further comprise a controller coupled to the energysource and configured to transmit parameters for the stimulationprotocol to the energy source. The controller and/or the energy sourcemay be wirelessly coupled to the electrodes, or each other.Alternatively, the controller and the energy source may be housed withinthe patch or the handheld device.

In another aspect, the present disclosure involves devices and methodsfor treating the symptoms of patient's in intensive or critical, such asthose patients who have recently suffered heart, lung or kidney failure,a stroke or a transient ischemic attack (TIA). A method comprisescontacting one or more electrodes to an outer skin surface of a neck ofthe patient and generating an electrical impulse with an energy source.The electrical impulse is transmitted transcutaneously andnon-invasively from the electrodes through the outer skin surface of thepatient to a vagus nerve in the patient for at least 30 seconds within 6hours of a commencement of symptoms, such as ischemia in the patient asa result of the stroke or TIA. The electrical impulse is sufficient tomodify the vagus nerve such that one or more of the symptoms are reducedor otherwise improved.

In one embodiment, the electrical impulse is transmitted for at least 30seconds within 4 hours of a commencement of symptoms in the patient. Theelectrical impulse may be applied in a single dose for a time period ofabout 30 seconds and about 3 minutes, preferably about 90-150 seconds,or it may be applied in a series of doses each having a time period ofabout 30 seconds to about 3 minutes, preferably about 90-150 seconds ineach dose. The series of doses may be applied every 5 to 30 minutes,preferably every 10 to 20 minutes, and more preferably every 15 minutes,for a period of at least 1 hour, preferably at least 2 hours and morepreferably about 3 hours. Each dose may be further applied every 6 to 10hours for a period of at least 2 to 10 days, preferably about 2 to 5days.

In another embodiment, the electrical impulse is applied in a first dosefor a time period of about 30 seconds and about 3 minutes, preferablyabout 90-150 seconds and then a second dose for a time period of about30 seconds and about 3 minutes, preferably about 90-150 seconds. Theelectrical impulse may be transmitted in a series of first and seconddoses, wherein the electrical impulse is applied for a time period ofabout 30 seconds to about 3 minutes (preferably about 90-150 seconds) ineach of the first and second doses. The first and second doses may beapplied every 10 to 30 minutes (preferably about every 15 minutes) for aperiod of at least at least 1 hour, preferably at least 2 hours and morepreferably about 3 hours. Each dose may be further applied every 6 to 10hours for a period of at least 2 to 10 days, preferably for about 2 to 5days.

Applicant has discovered that non-invasive electrical stimulation of thevagus nerve within six hours or less of the commencement of ischemiareduces the symptoms of the ischemia. In particular, applicant hasdiscovered that the overall infarct volume (i.e. the volume of deadtissue resulting from failure of blood supply) can be reduced in as adirect result of such electrical stimulation. Reducing the infarctvolume from ischemia improves the outcomes of patients suffering fromthis disorder. For example, reducing of infarct volume is typicallyassociated with improved neurological scores and forelimb grip strength,among other symptoms.

In certain embodiments, the energy source is wirelessly coupled to theone or more electrodes. In other embodiments, the energy source iscoupled to the electrodes directly with electrical connectors. In yetother embodiments, the energy source and the electrodes are housingwithin a handheld device that can be placed or attached against theouter surface of the patient's neck.

In one such embodiment, the electrodes are adhered to the outer skinsurface of the patient's neck with a suitable adhesive. This allows thepatient to be treated without direct intervention (i.e., holding adevice or the electrodes against the patient's neck during stimulation).The system may further comprise an outer sheath or other wearabledevice, such as a insulating strip, a collar, or a garment, such as aturtleneck, a scarf or the like, that functions to adhere the electrodesto the neck of the patient. The electrodes may be housed within thewearable device, or positioned between the wearable device and the neckof the patient.

In certain embodiments, the method may further comprise providingparameters for a stimulation protocol to the energy source. Theparameters may include the treatment regimen described above, or theymay include other parameters, such as the voltage, amplitude, dutycycle, frequency or duration of the electrical impulse or the overallelectrical stimulation. Alternatively or additionally, the positionand/or orientation of the stimulation device on the patient's neck maybe adjusted based on the physiological parameter. In certainembodiments, the device may be alternated between the right and leftside of the patient's neck to optimize the signal based on themeasurement of physiological parameters.

In certain embodiments, the method further comprises measuring one ormore physiological parameters of the patient associated with theelectrical impulse and modifying the parameters of the electricalimpulse based on the physiological parameter. Physiogical parameters mayinclude, for example, blood flow associated with a nerve, such as vagalartery or cerebral blood flow, heart rate variability, selectedbiomarkers or other chemicals, a property of a voice of the patient, alaryngeal electromyographic signal, an electroglottographic signal, aproperty of the autonomic nervous system and the like. The one or moreelectrodes may comprise two electrodes that are either attached to eachother, or separate from each other. In certain embodiments, the systemcomprises multiple sets of electrodes that can be positioned atdifferent locations on a patient's neck. The controller is configured todetermine, based on detection of a physiological response, which set orsets of electrodes produce optimal results, e.g., stimulation of thevagus nerve. In this embodiment, the controller is configured to directthe electrical impulses from the energy source to the optimallypositioned electrodes on the neck of the patient.

In certain embodiments, the electrical impulse comprises pulses having afrequency of about 1 kHZ to about 10 kHz. The electrical impulse maycomprise bursts of pulses, with each burst having a frequency of about 1to about 100 bursts per second or about 15 to 50 bursts per second andeach pulse has a duration of about 50 to about 1000 microseconds induration. The bursts may comprise about 2 to 20 pulses and the burstsmay be separated by an inter-burst period that comprises zero pulses,such that the inter-burst period has a constant electric field. Theconstant electric field may have a magnitude of zero.

Various technologies for preventing, diagnosing, monitoring,ameliorating, or treating medical conditions, diseases, or disorders,such as replicating pathogens, are more completely described in thefollowing detailed description, with reference to the drawings providedherewith, and in claims appended hereto. Other aspects, features,advantages, etc. will become apparent to one skilled in the art when thedescription is taken in conjunction with the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes asif copied and pasted herein, to the same extent as if each individualissued patent, published patent application, or non-patent publicationwere specifically and individually indicated to be incorporated byreference and copied and pasted into this disclosure.

DESCRIPTION OF DRAWINGS

FIG. 1 illustrates a schematic view of one embodiment of a nervemodulating system according to the present disclosure.

FIG. 2A shows an embodiment of an electrical voltage/current profile forstimulating and/or modulating impulses that are applied to a nerveaccording to this disclosure.

FIG. 2B illustrates an embodiment of a bursting electrical waveform forstimulating and/or modulating a nerve according to this disclosure.

FIG. 2C illustrates an embodiment of two successive bursts of thewaveform of FIG. 2B according to this disclosure.

FIG. 3A is a perspective view of a stimulator according to anotherembodiment of the present invention.

FIG. 3B is a cut-a-way view of the stimulator of FIG. 3A.

FIG. 3C is an exploded view of one of the electrode assemblies of thestimulator of FIG. 3A.

FIG. 3D is a cut-a-way view of the electrode assembly of FIG. 3C.

FIG. 4A is perspective view of the top of an alternative embodiment of astimulator according to the present invention.

FIG. 4B is a perspective view of the bottom of the stimulator of FIG.4A.

FIG. 4C is a cut-a-way view of the stimulator of FIG. 4A.

FIG. 4D is another cut-a-way view of the stimulator of FIG. 4A.

FIG. 5A is a front view of another embodiment of a stimulator accordingto this disclosure.

FIG. 5B is a back view of an embodiment of the stimulator shown in FIG.5A according to this disclosure.

FIG. 5C is a side view of an embodiment of the stimulator shown in FIG.5A according to this disclosure.

FIG. 6 shows an expanded diagram of an embodiment of a control unitaccording to the present disclosure.

FIG. 7 illustrates an embodiment of an approximate position of astimulator according to this disclosure, when used to stimulate a rightvagus nerve in a neck of an adult patient.

FIG. 8 illustrates an embodiment of an approximate position of astimulator according to this disclosure, when used to stimulate a rightvagus nerve in a neck of a child who wears a collar to hold thestimulator.

FIG. 9 illustrates an embodiment of a stimulator according to thisdisclosure, when positioned to stimulate a vagus nerve in a patient'sneck, wherein the stimulator is applied to a surface of the neck in avicinity of various identified anatomical structures.

FIG. 10 illustrates an embodiment of mechanisms or pathways throughwhich stimulation of the vagus nerve may reduce inflammation in patientswith neurodegenerative or autoimmune disorders according to thisdisclosure.

FIG. 11 illustrates an embodiment of another mechanism of action of amedical device in which sympathetic fibers release norepinephrine into aspleen in close proximity to a specialized group of immune cells thatrelease acetylcholine, or ACh according to this disclosure.

FIG. 12 illustrates a system for modulating the vagus nerve according tothe present disclosure.

FIG. 13 illustrates another embodiment of the present disclosure,wherein first and second electrodes are positioned on an outer surfaceof the patient's neck.

FIG. 14A illustrates yet another embodiment of the present disclosure,wherein a wearable device is positioned on an outer surface of thepatient's neck.

FIG. 14B illustrates a representative electrode of the embodiments ofFIGS. 13 and 14A.

FIG. 14C illustrates a representative electrode and a representativelead of the embodiments of FIGS. 14A and 14B.

FIG. 15 illustrates another embodiment of a stimulator device accordingto the present disclosure.

FIG. 16A is a schematic diagram of an embodiment of a system containinga medical device and an input device according to this disclosure.

FIG. 16B is a schematic diagram of an embodiment of a system containinga neurostimulator and a reader according to this disclosure.

FIG. 16C is a schematic diagram of an embodiment of a system containinga neurostimulator and a transceiver according to this disclosure.

FIG. 17 is a schematic diagram of an embodiment of a network diagram forinitially provisioning and refilling a system containing a medicaldevice according to this disclosure.

FIG. 18 is a flowchart of an embodiment of a method for initiallyprovisioning a system containing a medical device according to thisdisclosure.

FIG. 19 is a flowchart of an embodiment of a method for refilling asystem containing a medical device according to this disclosure.

FIG. 20 is a flowchart of an embodiment of a method for using a systemcontaining a medical device according to this disclosure.

DETAILED DESCRIPTION

Generally, this disclosure relates to the delivery of electricalimpulses (and/or fields) to bodily tissues for therapeutic purposes, andmore specifically to vagal nerve stimulation devices for treatingpatient's suffering from post-operative symptoms following major surgeryand/or for treating patients in critical or intensive care.

Critical or intensive care is the specialized care of patients whoseconditions are life-threatening and who require comprehensive care andconstant monitoring, usually in intensive care units. Such conditionsmay include stroke, transient ischemic attack (TIA), heart, liver,kidney or respiratory failure, shock, heart attack, sepsis, severeburns, severe bleeding, severe illnesses (e.g., COVID-19) and the like.In some embodiments, the systems and methods of the present disclosuremay be used to treat symptoms of ischemic stroke, such as the reductionof infarct volume immediately following an acute stroke when the bloodsupply to the brain is disrupted.

Post-operative symptoms may include nausea, vomiting, constipation, gas,post-operative ileus, post-operative pain, restlessness, sleeplessnessand the like. In some embodiments, the systems and methods of thepresent disclosure are particularly useful for mitigating or eliminatingthe impairment of gastrointestinal (GI) motility after intra-abdominalor nonabdominal surgery, such as post-operative ileus (POI).

In some embodiments, the systems and methods may reduce opioid-inducedof intestinal transit to improve motility, thereby allowing fasterrelease of patient's from the hospital. Reduction of post-operative painmay reduce the patient's reliance on postsurgical opioid pain relievers(e.g., morphine), which can slow or inhibit normal motility. This, inturn, may increase motility and/or reduce the symptoms of POI in thepatient, thereby allowing faster release of the patient from thehospital following surgery.

In some embodiments, the systems and methods may reduceinflammatory-induced dysfunction of intestinal transit to improvemotility. The device and methods of the present disclosure may reduceintestinal inflammation and accelerate the recovery of bowel functionvia a cholinergic anti-inflammatory pathway in the gut. Vagal efferentslocated in the bowel wall interact with macrophages (probably viaenteric neurons) to reduce the expression of inflammatory mediators anddecrease smooth muscle dysfunction. The devices of the presentdisclosure may also increase cardiac vagal tone and reduce markers ofsystematic inflammation. This increases intestinal transit and preventsboth systematic and intestinal inflammation.

VNS has been shown to be a potent moderator of pathologic immunereactions, specifically suppressing inflammatory cytokine levels viaactivation of the Cholinergic Anti-inflammatory Pathway (CAP). The CAPis believed to be the efferent vagus nerve-based arm of the inflammatoryreflex, mediated through vagal efferent fibers that synapse onto entericneurons, which release acetylcholine (Ach) at the synaptic junction withmacrophages. Stimulation of the CAP leads to Ach binding toα-7-nicotinic ACh receptors (α7nAChR), resulting in reduced productionof the inflammatory cytokines TNF-a, IL-1b, and IL-6, but not theanti-inflammatory cytokine, IL-10. VNS appears to decrease theproduction of inflammatory cytokines and consequently mitigate theinflammatory response. These cytokines are believed to play a role inthe acute exacerbation of respiratory symptoms.

Note though that this disclosure is now described more fully withreference to the set of accompanying illustrative drawings, in whichexample embodiments of this disclosure are shown. This disclosure can beembodied in many different forms and should not be construed asnecessarily being limited to the example embodiments disclosed herein.Rather, the example embodiments are provided so that this disclosure isthorough and complete, and fully conveys various concepts of thisdisclosure to those skilled in a relevant art. For example, the energyimpulses (and/or fields) that are used to treat those conditionscomprise electrical and/or electromagnetic energy, can be deliveredinvasively or non-invasively to the patient, particularly to a vagusnerve of the patient.

In some embodiments, the devices and methods of the present inventionstimulate nerves by transmitting energy to nerves and tissuenon-invasively. A medical procedure can be understood as beingnon-invasive when no break in the skin (or other surface of the body,such as a wound bed) is created through use of the method, and whenthere is no contact with an internal body cavity beyond a body orifice(e.g., beyond the mouth or beyond the external auditory meatus of theear). In some ways, such non-invasive procedures can be distinguishedfrom some invasive procedures (including minimally invasive procedures)in that the invasive procedures insert a substance or device into orthrough the skin (or other surface of the body, such as a wound bed) orinto an internal body cavity beyond a body orifice.

For example, transcutaneous electrical stimulation of a nerve can benon-invasive because it involves attaching electrodes to the skin, orotherwise stimulating at or beyond the surface of the skin or using aform-fitting conductive garment, without breaking the skin [ThierryKELLER and Andreas Kuhn. Electrodes for transcutaneous (surface)electrical stimulation. Journal of Automatic Control, University ofBelgrade 18(2, 2008):35-45, the disclosure of which is incorporatedherein by reference for all purposes as if copied and pasted herein;Mark R. PRAUSNITZ. The effects of electric current applied to skin: Areview for transdermal drug delivery. Advanced Drug Delivery Reviews 18(1996) 395-425, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein]. In contrast,percutaneous electrical stimulation of a nerve can be minimally invasivebecause it involves the introduction of an electrode under the skin, vianeedle-puncture of the skin.

Another form of non-invasive electrical stimulation is magneticstimulation. It involves the induction, by a time-varying magneticfield, of electrical fields and current within tissue, in accordancewith Faraday's law of induction. Magnetic stimulation can benon-invasive because the magnetic field is produced by passing atime-varying current through a coil positioned outside the body. Anelectric field is induced at a distance, causing electric current toflow within electrically conducting bodily tissue. The electricalcircuits for magnetic stimulators can be generally complex and expensiveand use a high current impulse generator that may produce dischargecurrents of 5,000 amps or more, which is passed through the stimulatorcoil to produce a magnetic pulse. Some principles of electrical nervestimulation using a magnetic stimulator, along with descriptions ofmedical applications of magnetic stimulation, are reviewed in: ChrisHOVEY and Reza Jalinous, The Guide to Magnetic Stimulation, The MagstimCompany Ltd, Spring Gardens, Whitland, Carmarthenshire, SA34 OHR, UnitedKingdom, 2006, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein. In contrast,the magnetic stimulators that are disclosed herein are relativelysimpler devices that can use considerably smaller currents within thestimulator coils. Accordingly, they are intended to satisfy a need forsimple-to-use and less expensive non-invasive magnetic stimulationdevices.

Some advantages of some of such non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures can be generally measurably painless and may beperformed without some of the dangers and costs of surgery. They areordinarily performed even without the need for local anesthesia. Lesstraining may be required for use of non-invasive procedures by medicalprofessionals. In view of the reduced risk ordinarily associated withnon-invasive procedures, some such procedures may be suitable for use bythe patient or family members at home or by first-responders at home orat a workplace. Furthermore, the cost of non-invasive procedures may besignificantly reduced relative to comparable invasive procedures.

In co-pending, commonly assigned patent applications, the Applicantdisclosed some noninvasive electrical vagus nerve stimulation devices,which are adapted, and for certain applications improved, in the presentdisclosure [application Ser. No. 13/183,765 and PublicationUS2011/0276112, entitled Devices and methods for non-invasive capacitiveelectrical stimulation and their use for vagus nerve stimulation on theneck of a patient, to SIMON et al, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein: application Ser. No. 12/964,050 and Publication No.US2011/0125203, entitled Magnetic Stimulation Devices and Methods ofTherapy, to SIMON et al, the disclosure of which is incorporated hereinby reference for all purposes as if copied and pasted herein; and otherco-pending commonly assigned applications that are cited therein, thedisclosure of which is incorporated herein by reference for all purposesas if copied and pasted herein]. At least some of the present disclosureelaborates on the electrical stimulation device, rather than themagnetic stimulation device that has similar functionality, with theunderstanding that unless it is otherwise indicated, the elaborationcould apply to either the electrical or the magnetic nerve stimulationdevice. Because some properties of some of the earlier devices havealready been disclosed, the present disclosure focuses on what is newwith respect to the earlier disclosures.

The patient can apply the stimulator without the benefit of having atrained healthcare provider nearby. An advantage of the self-stimulationtherapy is that it can be administered more or less immediately whensymptoms occur, rather than having to visit the healthcare provider at aclinic or emergency room. A need for such a visit would only compoundthe aggravation that the patient is already experiencing. Anotheradvantage of the self-stimulation therapy is the convenience ofproviding the therapy in the patient's home or workplace, whicheliminates scheduling difficulties, for example, when the nervestimulation is being administered for prophylactic reasons at odd hoursof the day. Furthermore, the cost of the treatment may be reduced by notrequiring the involvement of a trained healthcare provider.

The present disclosure discloses methods and devices for thenon-invasive treatment of diseases and disorders, utilizing an energysource that transmits energy non-invasively to nervous tissue. Inparticular, the devices can transmit energy to, or in close proximityto, a nerve of the patient, such as the vagus nerve, in order totemporarily stimulate, block and/or modulate electrophysiologicalsignals in that nerve. In some embodiments, some electrodes applied tothe skin of the patient generate currents within the tissue of thepatient. This may enable production and application of the electricalimpulses so as to interact with the signals of one or more nerves, inorder to achieve the therapeutic result. Some of the disclosure isdirected specifically to treatment of a patient by stimulation in oraround a vagus nerve, with devices positioned non-invasively on or neara patient's neck to treat patients in critical care such as thosepatient's suffering post-operative symptoms following major surgeryand/or patient's suffering from other critical conditions, such asischemic stroke, TIA and the like.

However, other medical devices, techniques, and modalities ofprevention, diagnosis, monitoring, amelioration, or treatment of variousmedical conditions, disorders, or diseases are disclosed herein as well.For example, the system and methods of the present disclosure may alsobe configured to prevent, diagnose, monitor, ameliorate, or treat aneurological condition, such as epilepsy, headache/migraine, whetherprimary or secondary, whether cluster or tension, neuralgia, seizures,vertigo, dizziness, concussion, aneurysm, palsy, Parkinson's disease,Alzheimer's disease, or others, as understood to skilled artisans andwhich are only omitted here for brevity. For example, some systems andmethods can be configured to prevent, diagnose, monitor, ameliorate, ortreat a neurodegenerative disease, such as Alzheimer's disease,Parkinson's disease, multiple sclerosis, postoperative cognitivedysfunction, and postoperative delirium, or others, as understood toskilled artisans and which are only omitted here for brevity.

For example, some systems and methods can be configured to prevent,diagnose, monitor, ameliorate, or treat an inflammatory disease ordisorder, such as Alzheimer's disease, ankylosing spondylitis, arthritis(osteoarthritis, rheumatoid arthritis (RA), Sjôgren's syndrome, temporalarteritis, Type 2 diabetes, psoriatic arthritis, asthma,atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis,fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupuserythematous (SLE), nephritis, fibromyalgia, Celiac disease, Parkinson'sdisease, ulcerative colitis, chronic peptic ulcer, tuberculosis,periodontitis, sinusitis, hepatitis, Graves' disease, psoriasis,pernicious anemia (PA), peripheral neuropathy, lupus or others, asunderstood to skilled artisans and which are only omitted here forbrevity.

For example, some systems and methods can be configured to prevent,diagnose, monitor, ameliorate, or treat a gastrointestinal condition,such as ileus, irritable bowel syndrome, Crohn's disease, ulcerativecolitis, diverticulitis, gastroesophageal reflux disease, or others, asunderstood to skilled artisans and which are only omitted here forbrevity. For example, some systems and methods can be configured toprevent, diagnose, monitor, ameliorate, or treat a bronchial disorder,such as asthma, bronchitis, pneumonia, or others, as understood toskilled artisans and which are only omitted here for brevity.

For example, some systems and methods can be configured to prevent,diagnose, monitor, ameliorate, or treat a coronary artery disease, heartattack, arrhythmia, cardiomyopathy, or others, as understood to skilledartisans and which are only omitted here for brevity. For example, somesystems and methods can be configured to prevent, diagnose, monitor,ameliorate, or treat a urinary disorder, such as urinary incontinence,urinalysis, overactive bladder, or others, as understood to skilledartisans and which are only omitted here for brevity.

For example, some systems and methods can be configured to prevent,diagnose, monitor, ameliorate, or treat eat a cancer, such as bladdercancer, breast cancer, prostate cancer, lung cancer, colon or rectalcancer, skin cancer, thyroid cancer, brain cancer, leukemia, livercancer, lymphoma, pancreatic cancer, or others, as understood to skilledartisans and which are only omitted here for brevity. For example, somesystems and methods can be configured to prevent, diagnose, monitor,ameliorate, or treat a metabolic disorder, such as diabetes (type 1,type 2, or gestational), Gaucher's disease, sick cell anemia, cysticfibrosis, hemochromatosis, or others, as understood to skilled artisansand which are only omitted here for brevity.

As a preliminary matter, we first describe the vagus nerve itself andits most proximal connections, which are relevant to the disclosurebelow of the electrical waveforms that may be used to perform some ofthe stimulation. A fact that electrical stimulation of a vagus nerve canbe used to treat many disorders may be understood as follows. The vagusnerve is composed of motor and sensory fibers. The vagus nerve leavesthe cranium, passes down the neck within the carotid sheath to the rootof the neck, then passes to the chest and abdomen, where it contributesto the innervation of the viscera. A human vagus nerve (tenth cranialnerve, paired left and right) comprises of over 100,000 nerve fibers(axons), mostly organized into groups. The groups are contained withinfascicles of varying sizes, which branch and converge along the nerve.Under normal physiological conditions, each fiber conducts electricalimpulses only in one direction, which is defined to be the orthodromicdirection, and which is opposite the antidromic direction. However,external electrical stimulation of the nerve may produce actionpotentials that propagate in orthodromic and antidromic directions.Besides efferent output fibers that convey signals to the various organsin the body from the central nervous system, the vagus nerve conveyssensory (afferent) information about the state of the body's organs backto the central nervous system. Some 80-90% of the nerve fibers in thevagus nerve are afferent (sensory) nerves, communicating the state ofthe viscera to the central nervous system.

The largest nerve fibers within a left or right vagus nerve areapproximately 20 μm in diameter and are heavily myelinated, whereas onlythe smallest nerve fibers of less than about 1 μm in diameter arecompletely unmyelinated. When the distal part of a nerve is electricallystimulated, a compound action potential may be recorded by an electrodelocated more proximally. A compound action potential contains severalpeaks or waves of activity that represent the summated response ofmultiple fibers having similar conduction velocities. The waves in acompound action potential represent different types of nerve fibers thatare classified into corresponding functional categories, withapproximate diameters as follows: A-alpha fibers (afferent or efferentfibers, 12-20 μm diameter), A-beta fibers (afferent or efferent fibers,5-12 μm), A-gamma fibers (efferent fibers, 3-7 μm), A-delta fibers(afferent fibers, 2-5 μm), B fibers (1-3 μm) and C fibers (unmyelinated,0.4-1.2 μm). The diameters of group A and group B fibers include thethickness of the myelin sheaths.

The vagus (or vagal) afferent nerve fibers arise from cell bodieslocated in the vagal sensory ganglia, which take the form of swellingsnear the base of the skull. Vagal afferents traverse the brainstem inthe solitary tract, with some eighty percent of the terminating synapsesbeing located in the nucleus of the tractus solitarius (or nucleustractus solitarii, nucleus tractus solitarius, or NTS). The NTS projectsto a wide variety of structures in the central nervous system, such asthe amygdala, raphe nuclei, periaqueductal gray, nucleusparagigantocellurlais, olfactory tubercule, locus ceruleus, nucleusambiguus and the hypothalamus. The NTS also projects to the parabrachialnucleus, which in turn projects to the hypothalamus, the thalamus, theamygdala, the anterior insula, and infralimbic cortex, lateralprefrontal cortex, and other cortical regions [JEAN A. The nucleustractus solitarius: neuroanatomic, neurochemical and functional aspects.Arch Int Physiol Biochim Biophys 99(5, 1991):A3-A52 the disclosure ofwhich is incorporated herein by reference for all purposes as if copiedand pasted herein]. Thus, stimulation of vagal afferents can modulatethe activity of many structures of the brain and brainstem through theseprojections.

With regard to vagal efferent nerve fibers, two vagal components haveevolved in the brainstem to regulate peripheral parasympatheticfunctions. The dorsal vagal complex, consisting of the dorsal motornucleus and its connections controls parasympathetic function primarilybelow the level of the diaphragm, while the ventral vagal complex,comprised of nucleus ambiguus and nucleus retrofacial, controlsfunctions primarily above the diaphragm in organs such as the heart,thymus and lungs, as well as other glands and tissues of the neck andupper chest, and specialized muscles such as those of the esophagealcomplex. For example, the cell bodies for the preganglionicparasympathetic vagal neurons that innervate the heart reside in thenucleus ambiguus, which is relevant to potential cardiovascular sideeffects that may be produced by vagus nerve stimulation.

The vagus efferent fibers innervate parasympathetic ganglionic neuronsthat are located in or adjacent to each target organ. The vagalparasympathetic tone resulting from the activity of these fibers isbalanced reflexively in part by sympathetic innervations. Consequently,electrical stimulation of a vagus nerve may result not only inmodulation of parasympathetic activity in postganglionic nerve fibers,but also a reflex modulation of sympathetic activity. The ability of avagus nerve to bring about widespread changes in autonomic activity,either directly through modulation of vagal efferent nerves, orindirectly via activation of brainstem and brain functions that arebrought about by electrical stimulation of vagal afferent nerves,accounts for the fact that vagus nerve stimulation can treat manydifferent medical conditions in many end organs. Selective treatment ofparticular conditions is possible because the parameters of theelectrical stimulation (e.g. frequency, amplitude, pulse width, etc.)may selectively activate or modulate the activity of particular afferentor efferent A, B, and/or C fibers that result in a particularphysiological response in each individual.

The electrodes used to stimulate a vagus nerve can be implanted aboutthe nerve during open neck surgery. For many patients, this may be donewith an objective of implanting permanent electrodes to treat epilepsy,depression, or other conditions [Arun Paul AMAR, Michael L. Levy,Charles Y. Liu and Michael L. J. Apuzzo. Chapter 50. Vagus nervestimulation. pp. 625-638, the disclosure of which is incorporated hereinby reference for all purposes as if copied and pasted herein. In: ElliotS. Krames, P. Hunber Peckham, Ali R. Rezai, eds. Neuromodulation.London: Academic Press, 2009, the disclosure of which is incorporatedherein by reference for all purposes as if copied and pasted herein;KIRSE D J, Werle A H, Murphy J V, Eyen T P, Bruegger D E, Hornig G W,Torkelson R D. Vagus nerve stimulator implantation in children. ArchOtolaryngol Head Neck Surg 128(11, 2002):1263-1268, the disclosure ofwhich is incorporated herein by reference for all purposes as if copiedand pasted herein]. In that case, the electrode can be a spiralelectrode, although other designs may be used as well [U.S. Pat. No.4,979,511, entitled Strain relief tether for implantable electrode, toTERRY, Jr., the disclosure of which is incorporated herein by referencefor all purposes as if copied and pasted herein; U.S. Pat. No.5,095,905, entitled Implantable neural electrode, to KLEPINSKI, thedisclosure of which is incorporated herein by reference for all purposesas if copied and pasted herein]. In other patients, a vagus nerve can beelectrically stimulated during an open-neck thyroid surgery in order toconfirm that the nerve has not been accidentally damaged during thesurgery. In that case, a vagus nerve in the neck is surgically exposed,and a temporary stimulation electrode is clipped about the nerve[SCHNEIDER R, Randolph G W, Sekulla C, Phelan E, Thanh P N, Bucher M,Machens A, Dralle H, Lorenz K. Continuous intraoperative vagus nervestimulation for identification of imminent recurrent laryngeal nerveinjury. Head Neck. 2012 Nov. 20. doi: 10.1002/hed.23187 (Epub ahead ofprint, pp. 1-8), the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein].

It is also possible to electrically stimulate a vagus nerve using aminimally invasive surgical approach, namely percutaneous nervestimulation. In that procedure, a pair of electrodes (an active and areturn electrode) are introduced through the skin of a patient's neck tothe vicinity of a vagus nerve, and wires connected to the electrodesextend out of the patient's skin to a pulse generator [Publicationnumber US20100241188, entitled Percutaneous electrical treatment oftissue, to J. P. ERRICO et al., the disclosure of which is incorporatedherein by reference for all purposes as if copied and pasted herein;SEPULVEDA P, Bohill G, Hoffmann T J. Treatment of asthmaticbronchoconstriction by percutaneous low voltage vagal nerve stimulation:case report. Internet J Asthma Allergy Immunol 7(2009):e1 (pp 1-6), thedisclosure of which is incorporated herein by reference for all purposesas if copied and pasted herein; MINER, J. R., Lewis, L. M., Mosnaim, G.S., Varon, J., Theodoro, D. Hoffman, T. J. Feasibility of percutaneousvagus nerve stimulation for the treatment of acute asthma exacerbations.Acad Emerg Med 2012; 19: 421-429, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein].

Percutaneous nerve stimulation procedures has been somewhat describedprimarily for the treatment of pain, but not for a vagus nerve, which isordinarily not considered to produce pain and which presents specialchallenges [HUNTOON M A, Hoelzer B C, Burgher A H, Hurdle M F, Huntoon EA. Feasibility of ultrasound-guided percutaneous placement of peripheralnerve stimulation electrodes and anchoring during simulated movement:part two, upper extremity. Reg Anesth Pain Med 33(6, 2008):558-565, thedisclosure of which is incorporated herein by reference for all purposesas if copied and pasted herein; CHAN I, Brown A R, Park K, Winfree C J.Ultrasound-guided, percutaneous peripheral nerve stimulation: technicalnote. Neurosurgery 67(3 Suppl Operative, 2010):ons136-139, thedisclosure of which is incorporated herein by reference for all purposesas if copied and pasted herein; MONTI E. Peripheral nerve stimulation: apercutaneous minimally invasive approach. Neuromodulation 7(3,2004):193-196, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein; Konstantin VSLAVIN. Peripheral nerve stimulation for neuropathic pain. US Neurology7(2, 2011):144-148, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein].

In some embodiments, a stimulation device is introduced through apercutaneous penetration in the patient to a target location within,adjacent to, or in close proximity with, the carotid sheath thatcontains the vagus nerve. Once in position, electrical impulses areapplied through the electrodes of the stimulation device to one or moreselected nerves (e.g., vagus nerve or one of its branches) to stimulate,block or otherwise modulate the nerve(s) and treat the patient'scondition or a symptom of that condition. For some conditions, thetreatment may be acute, meaning that the electrical impulse immediatelybegins to interact with one or more nerves to produce a response in thepatient. In some cases, the electrical impulse will produce a responsein the nerve(s) to improve the patient's condition or symptom in lessthan 3 hours, preferably less than 1 hour and more preferably less than15 minutes. For other conditions, intermittently scheduled or as-neededstimulation of the nerve may produce improvements in the patient overthe course of several hours, days, weeks, months or years. A morecomplete description of a suitable percutaneous procedure for vagalnerve stimulation can be found in commonly assigned, co-pending USpatent application titled “Percutaneous Electrical Treatment of Tissue”,filed Apr. 13, 2009 (Ser. No. 12/422,483), the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein.

In some embodiments, a time-varying magnetic field, originating andconfined to the outside of a patient, generates an electromagnetic fieldand/or induces eddy currents within tissue of the patient. In someembodiments, electrodes applied to the skin of the patient generatecurrents within the tissue of the patient. In some embodiments, anobjective may include an ability to produce and apply the electricalimpulses so as to interact with the signals of one or more nerves, totreat patient's suffering post-operative symptoms following majorsurgery and/or for treating patients in critical or intensive care, suchas those patient's suffering from stroke, transient ischemic attack(TIA), heart, kidney or respiratory failure, shock, sepsis, severeburns, severe illnesses (e.g., COVID-19) and the like.

Some of the disclosure is directed specifically to treatment of apatient by electromagnetic stimulation in or around a vagus nerve, withdevices positioned non-invasively on or near a patient's neck. However,it will also be appreciated that some the devices and methods can beapplied to other tissues and nerves of the body, including but notlimited to other parasympathetic nerves, sympathetic nerves, spinal orcranial nerves. As recognized by those having skill in the art, themethods should be carefully evaluated prior to use in patients known tohave preexisting cardiac issues. In addition, it will be recognized thatsome of the treatment paradigms can be used with a variety of differentvagal nerve stimulators, including implantable and/or percutaneousstimulation devices, such as the ones described herein.

In some embodiments, broadly speaking, the Applicant has determined thatthere are several components to the effects of nVNS on the brain. Forexample, the strongest effect occurs during the acute stimulation andresults in significant changes in brain function that can be clearlyseen as acute changes in autonomic function (e.g. measured usingpupillometry, heart rate variability, galvanic skin response, or evokedpotential) and activation and inhibition of various brain regions asshown in fMRI imaging studies. For example, the second effect ofmoderate intensity, lasts for 15 to 180 minutes after stimulation.Animal studies have shown changes in neurotransmitter levels in variousparts of the brain that persist for several hours. For example, thethird effect of mild intensity, lasts up to 8 hours and is responsiblefor the long lasting alleviation of symptoms seen clinically and, forexample, in animal models of migraine headache and autoimmune diseases,such as Sjôgren's syndrome and Rheumatoid arthritis or RA.

Treatment Paradigms

Thus, depending on the medical indication, whether it is a chronic oracute treatment, and the natural history of the disease, differenttreatment protocols may be used. In particular, applicant has discoveredthat it is not necessary to “continuously stimulate” the vagus nerve (orto in order to provide clinically efficacious benefits to patients withcertain disorders. The term “continuously stimulate” as defined hereinmeans stimulation that follows a certain On/Off pattern continuously 24hours/day. For example, existing implantable vagal nerve stimulators“continuously stimulate” the vagus nerve with a pattern of 30 secondsON/5 minutes OFF (or the like) for 24 hours/day and seven days/week.Applicant has determined that this continuous stimulation is notnecessary to provide the desired clinical benefit for many disorders.

The present invention contemplates three types of interventionsinvolving stimulation of a vagus nerve: prophylactic, acute andcompensatory (rehabilitative). Among these, the acute treatment involvesthe fewest administrations of vagus nerve stimulations, which begin uponthe appearance of symptoms. It is intended primarily to enlist andengage the autonomic nervous system to inhibit excitatoryneurotransmissions that accompany the symptoms. The prophylactictreatment resembles the acute treatment in the sense that it isadministered as though acute symptoms had just occurred (even thoughthey have not) and is repeated at regular intervals, as though thesymptoms were reoccurring (even though they are not). The rehabilitativeor compensatory treatments, on the other hand, seek to promote long-termadjustments in the central nervous system, compensating for deficienciesthat arose as the result of the patient's disease by making new neuralcircuits.

A vagus nerve stimulation treatment according to the present inventionis conducted for continuous period of thirty seconds to five minutes,preferably about 90 seconds to about three minutes and more preferablyabout two minutes (each defined as a single dose). After a dose has beencompleted, the therapy is stopped for a period of time (depending on thetreatment as described below). For prophylactic treatments, such as atreatment to avert a stroke or transient ischemic attack or for treatingpatient's prior to a major surgery, the therapy preferably comprisesmultiple doses/day over a period of time that may last from one day to anumber of months or even years. In certain embodiments, the treatmentwill comprise multiple doses at predetermined times during the dayand/or at predetermined intervals throughout the day. In exemplaryembodiments, the treatment comprises one of the following: (1) 3doses/day at predetermined intervals or times; (2) two doses, eitherconsecutively, or separated by 5 min at predetermined intervals ortimes, preferably two or three times/day; (3) 3 doses, eitherconsecutively or separated by 5 min again at predetermined intervals ortimes, such as 2 or 3 times/day; or (4) 1-3 doses, either consecutivelyor separated by 5 min, 4-6 times per day. Initiation of a treatment maybegin 2 to 5 days prior to a major surgery or when an imminent stroke orTIA is forecasted, or in a risk-factor reduction program it may beperformed throughout the day beginning after the patient arises in themorning.

For treatment of patients undergoing major surgery to alleviatepost-operative symptoms, such as POI, the treatment protocol maycomprise a combination or acute and chronic treatments. The therapypreferably comprises multiple doses/day over a period of time that maylast 2 to 10 days. In some cases, the treatment protocol includesadministering multiple single doses for a period of about 2 to about 5days following surgery. In other cases, the treatment protocol includesadministering multiple single doses for a period of about 2 to about 5days prior to and/or about 2 to about 5 days following surgery (or untilsymptoms improve or completely resolve). In exemplary embodiments, thetreatment comprises one of the following: (1) 2-12 doses/day, preferablyabout 2-4 doses, at predetermined intervals or times; (2) two doses,either consecutively, or separated by 5 min at predetermined intervalsor times, preferably two to four times/day; (3) 3 doses, eitherconsecutively or separated by 5 min again at predetermined intervals ortimes, such as 2 or 3 times/day; or (4) 1-3 doses, either consecutivelyor separated by 5 min, 4-6 times per day.

For certain disorders, the time of day can be more important than thetime interval between treatments. For example, the locus correleus hasperiods of time during a 24 hour day wherein it has inactive periods andactive periods. Typically, the inactive periods can occur in the lateafternoon or in the middle of the night when the patient is asleep. Itis during the inactive periods that the levels of inhibitoryneurotransmitters in the brain that are generated by the locus correleusare reduced. This may have an impact on certain disorders. For example,patients suffering from migraines or cluster headaches often receivethese headaches after an inactive period of the locus correleus. Forthese types of disorders, the prophylactic treatment is optimal duringthe inactive periods such that the amounts of inhibitoryneurotransmitters in the brain can remain at a higher enough level tomitigate or abort an acute attack of the disorder.

In these embodiments, the prophylactic treatment may comprise multipledoses/day timed for periods of inactivity of the locus correleus. In oneembodiment, a treatment according to the present invention comprises oneor more doses administered 2-3 times per day or 2-3 “treatment sessions”per day. The treatment sessions preferably occur during the lateafternoon or late evening, in the middle of the night and again in themorning when the patient wakes up. In an exemplary embodiment, eachtreatment session comprises 1-4 doses, preferably 2-3 doses, with eachdose lasting for about 60 seconds to about 5 minutes, preferably about90 seconds to about three minutes.

For other disorders, the intervals between treatment sessions may be themost important as applicant has determined that stimulation of the vagusnerve can have a prolonged effect on the inhibitor neurotransmitterslevels in the brain, e.g., at least one hour, up to 3 hours andsometimes up to 8 hours. In one embodiment, a treatment according to thepresent invention comprises one or more doses (i.e., treatment sessions)administered at intervals during a 24 hour period. In a preferredembodiment, there are 1-5 such treatment sessions, preferably 2-4treatment sessions. Each treatment session preferably comprises 1-3doses, each “dose” lasting between about 60 seconds to about fiveminutes, preferably about 90 seconds to about 150 seconds, morepreferably about 2 minutes.

For an acute treatment of stroke, the therapy according to the presentinvention comprises at least 1 “dose” administered within about 6 hours,preferably about 5 hours and more preferably about 4 hours of the onsetof symptoms, or the commencement of ischemia in the patient.Alternatively, the therapy may include at least a first dose immediatelyfollowed by a second dose, with both the first and second dosesadministered within about 6 hours, preferably about 5 hours and morepreferably about 4 hours of the onset of symptoms, or the commencementof ischemia in the patient. As discussed below in the Example, Applicanthas discovered that non-invasive electrical stimulation of the vagusnerve within six hours or less of the commencement of ischemia reducesthe symptoms of the ischemia. In particular, applicant has discoveredthat the overall infarct volume (i.e. the volume of dead tissueresulting from failure of blood supply) can be reduced in as a directresult of such electrical stimulation. Reducing the infarct volume fromischemia improves the outcomes of patients suffering from this disorder.For example, reduction of infarct volume is typically associated withimproved neurological scores and forelimb grip strength, among othersymptoms.

The treatment regimen or stimulation protocol may further includefollow-on doses after the initial dose or doses discussed above.Applicant has further discovered that follow-on doses administered forat least one hour, preferably at least two hours and more preferablyabout 3 hours, results in improved symptoms from stroke, particularlyreduced infarct volumes. The doses may be administered continuously forthese time periods, more preferably, they may be administered aftercertain time intervals. In an exemplary embodiment, the time intervalsare about 5 to 30 minutes between each dose or doses, preferably betweenabout 10 to 20 minutes and more preferably every 15 minutes.

Applicant has also discovered that the treatment can be furtheroptimized with additional doses being administered with longer timeintervals after the first 1-3 hours. In an exemplary embodiment, theadditional doses are administered between about 6 to 10 hours apart,preferably about 8 hours, for at least two days, preferably betweenabout 2-5 days or until the patient is discharged from the hospital.

In an exemplary embodiment, Applicant has discovered a unique treatmentparadigm that is particularly effective for treating symptoms of stroke,such as reduction of infarction volume. In this treatment paradigm,first and second doses are administered within 6 hours of the onset ofsymptoms, preferably within 6 hours of the onset of ischemia resultingfrom the stroke. The first and second doses are each administered for aperiod of about 30 seconds to about 3 minutes, preferably about 2minutes. The second dose is preferably administered directly after thefirst dose (i.e., 0 minutes), or between about 1 minute and 15 minutesafter the first dose, preferably about 0 to 2 minutes. This pattern isthen continued every 10 to 20 minutes, preferably about every 15minutes, for a period of about 2 to 5 hours, preferably about 3 hours.For example, in one exemplary embodiment, the first and second doses areadministered for about 2 minutes each (2×2 minutes; referred to as a“treatment session)) and each treatment session is administered every 15minutes for 3 hours for a total of 13 such treatment sessions.

Upon conclusion of the first three hours, subsequent treatment sessionsmay be administered to the patient every 6 to 10 hours, preferably every8 hours. These subsequent treatment sessions are administered for aperiod of 2 to 5 days, or until the physician has determined that theinfarction is no longer increasing in volume or area within thepatient's brain.

The length of time for the initial series of doses (1-3 hours) and thefollow-on series of doses (2-5 days) can also be modified based on theclinical outcomes of individual patients. For example, in the event thata patient has recovered from the acute stroke or TIA, or in the eventthat the volume of infarct is no longer increasing (which generallymeans that the symptoms will no longer get worse), then the treatmentregimen can be halted before the full series of prescribed doses areadministered to the patient.

For long term treatment of an acute insult such as one that occursduring the rehabilitation of a stroke patient, the therapy may consistof: (1) 3 treatments/day; (2) 2 treatments, either consecutively orseparated by 5 min, 3×/day; (3) 3 treatments, either consecutively orseparated by 5 min, 2×/day; (4) 2 or 3 treatments, either consecutivelyor separated by 5 min, up to 10×/day; or (5) 1, 2 or 3 treatments,either consecutively or separated by 5 min, every 15, 30, 60 or 120 min.In an exemplary embodiment, each treatment session comprises 1-3 dosesadministered to the patient either consecutively or separated by 5minutes. The treatment sessions are administered every 15, 30, 60 or 120minutes during the day such that the patient could receive 2 doses everyhour throughout a 24 hour day.

For all of the treatments listed above, one may alternate treatmentbetween left and right sides, or in the case of stroke or migraine thatoccur in particular brain hemispheres, one may treat ipsilateral orcontralateral to the stroke-hemisphere or headache side, respectively.Or for a single treatment, one may treat one minute on one side followedby one minute on the opposite side. Variations of these treatmentparadigms may be chosen on a patient-by-patient basis. However, it isunderstood that parameters of the stimulation protocol may be varied inresponse to heterogeneity in the symptoms of patients. Differentstimulation parameters may also be selected as the course of thepatient's condition changes. In preferred embodiments, the disclosedmethods and devices do not produce clinically significant side effects,such as agitation or anxiety, or changes in heart rate or bloodpressure.

The prophylactic treatments may be most effective when the patient is ina prodromal, high-risk bistable state. In that state, the patient issimultaneously able to remain normal or exhibit symptoms, and theselection between normal and symptomatic states depends on theamplification of fluctuations by physiological feedback networks. Forexample, a thrombus may exist in either a gel or fluid phase, with thefeedback amplification of fluctuations driving the change of phaseand/or the volume of the gel phase. Thus, a thrombus may form or not,depending on the nonlinear dynamics exhibited by the network of enzymesinvolved in clot formation, as influenced by blood flow and inflammationthat may be modulated by vagus nerve stimulation [PANTELEEV M A,Balandina A N, Lipets E N, Ovanesov M V, Ataullakhanov F I.Task-oriented modular decomposition of biological networks: triggermechanism in blood coagulation. Biophys J 98(9, 2010):1751-1761; AlexeyM SHIBEKO, Ekaterina S Lobanova, Mikhail A Panteleev and Fazoil IAtaullakhanov. Blood flow controls coagulation onset via the positivefeedback of factor VII activation by factor Xa. BMC Syst Biol 2010;4(2010):5, pp. 1-12]. Consequently, the mechanisms of vagus nervestimulation treatment during prophylaxis for a stroke are generallydifferent than what occurs during an acute treatment, when thestimulation inhibits excitatory neurotransmission that follows the onsetof ischemia that is already caused by the thrombus. Nevertheless, theprophylactic treatment may also inhibit excitatory neurotransmission soas to limit the excitation that would eventually occur upon formation ofa thrombus, and the acute treatment may prevent the formation of anotherthrombus.

Description of Various Nerve Stimulating/Modulating Devices

Some devices that are used to stimulate a vagus nerve are now described.An embodiment is shown in FIG. 1 , which is a schematic diagram of anelectrode-based nerve stimulating and/or modulating device 302 fordelivering impulses of energy to nerves for the treatment of medicalconditions. As shown, device 302 may include an impulse generator 310;an energy or power source 320 coupled to the impulse generator 310; acontrol unit 330 in communication with the impulse generator 310 andcoupled to the energy source 320; and electrodes 340 coupled via wires345 to impulse generator 310. In some embodiments, the same impulsegenerator 310, energy source 320, and control unit 330 may be used foreither a magnetic stimulator or the electrode-based stimulator 302,allowing the user to change parameter settings depending on whethermagnetic coils or the electrodes 340 are attached.

Although a pair of electrodes 340 is shown in FIG. 1C, in practice theelectrodes may also comprise three or more distinct electrode elements,each of which is connected in series or in parallel to the impulsegenerator 310. Thus, the electrodes 340 that are shown in FIG. 1Crepresent some, most, many, or all electrodes of the devicecollectively.

In certain embodiments, device 302 may also include is a volume,contiguous with an electrode 340, that is filled with electricallyconducting medium 350. The conducting medium in which the electrode 340is embedded need not completely surround or extend about an electrode.The volume 350 is electrically connected to the patient at a target skinsurface in order to shape the current density passed through anelectrode 340 that is needed to accomplish stimulation of the patient'snerve or tissue. The electrical connection to the patient's skin surfaceis through an interface 351. In some embodiments, the interface is madeof an electrically insulating (dielectric) material, such as a thinsheet of Mylar. In that case, electrical coupling of the stimulator tothe patient is capacitive. In some embodiments, the interface compriseselectrically conducting material, such as the electrically conductingmedium 350 itself, an electrically conducting or permeable membrane, ora metal piece. In that case, electrical coupling of the stimulator tothe patient is ohmic. As shown, the interface may be deformable suchthat it is form fitting when applied to the surface of the body. Thus,the sinuousness or curvature shown at the outer surface of the interface351 corresponds also to sinuousness or curvature on the surface of thebody, against which the interface 351 is applied, so as to make theinterface and body surface contiguous.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's electrodes (or magnetic coils). Thesignals are selected to be suitable for amelioration of a particularmedical condition when the signals are applied non-invasively to atarget nerve or tissue via the electrodes 340. It is noted that nervestimulating/modulating device 302 may be referred to by its function asa pulse generator. Patent application publications US2005/0075701 andUS2005/0075702, both to SHAFER, the disclosure of which is incorporatedherein by reference for all purposes as if copied and pasted herein,contain descriptions of pulse generators that may be applicable to thisdisclosure. By way of example, a pulse generator is also commerciallyavailable, such as Agilent 33522A Function/Arbitrary Waveform Generator,Agilent Technologies, Inc., 5301 Stevens Creek Blvd Santa Clara Calif.95051.

The control unit 330 may comprise a general purpose computer, comprisingone or more CPU, computer memories for the storage of executablecomputer programs (including the system's operating system) and thestorage and retrieval of data, disk storage devices, communicationdevices (such as serial and USB ports) for accepting external signalsfrom a keyboard, computer mouse, and touchscreen, as well as anyexternally supplied physiological signals, analog-to-digital convertersfor digitizing externally supplied analog signals, communication devicesfor the transmission and receipt of data to and from external devicessuch as printers and modems that comprise part of the system, hardwarefor generating the display of information on monitors or display screensthat comprise part of the system, and busses to interconnect theabove-mentioned components. Thus, the user may operate the system bytyping or otherwise providing instructions for the control unit 330 at adevice such as a keyboard or touch-screen and view the results on adevice such as the system's computer monitor or display screen, ordirect the results to a printer, modem, and/or storage disk. Control ofthe system may be based upon feedback measured from externally suppliedphysiological or environmental signals. Alternatively, the control unit330 may have a compact and simple structure, for example, wherein theuser may operate the system using only an on/off switch and energycontrol wheel or knob, or their touchscreen equivalent. In a sectionbelow, an embodiment is also described wherein the stimulator housinghas a simple structure, but other components of the control unit 330 aredistributed into other devices (see FIG. 5 ).

Parameters for the nerve or tissue stimulation include energy level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes, as well as the spatial distribution ofthe electric field that is produced by the electrodes. The rise time andpeak energy are governed by the electrical characteristics of thestimulator and electrodes, as well as by the anatomy of the region ofcurrent flow within the patient. In some embodiments, pulse parametersare set in such a way as to account for the detailed anatomy surroundingthe nerve that is being stimulated [Bartosz SAWICKI, Robert Szmurło,Przemysław Płonecki, Jacek Starzyński, Stanisław Wincenciak, AndrzejRysz. Mathematical Modelling of Vagus Nerve Stimulation. pp. 92-97 in:Krawczyk, A. Electromagnetic Field, Health and Environment: Proceedingsof EHE'07. Amsterdam, IOS Press, 2008, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein]. Pulses may be monophasic, biphasic or polyphasic. Insome embodiments, some devices include those that are fixed frequency,where each pulse in a train has the same inter-stimulus interval, andthose that have modulated frequency, where the intervals between eachpulse in a train can be varied.

FIG. 2A illustrates an example of an electrical voltage/current profilefor a stimulating, blocking and/or modulating impulse applied to aportion or portions of selected nerves in accordance with an embodimentof this disclosure. For some embodiments, the voltage and current referto those that are non-invasively produced within the patient by theelectrodes (or magnetic coils). As shown, a suitable electricalvoltage/current profile 400 for the blocking and/or modulating impulse410 to the portion or portions of a nerve may be achieved using pulsegenerator 310. In some embodiments, the pulse generator 310 may beimplemented using an energy source 320 and a control unit 330 having,for instance, a processor, a clock, a memory, etc., to produce a pulsetrain 420 to the electrodes 340 that deliver the stimulating, blockingand/or modulating impulse 410 to the nerve. Nerve stimulating/modulatingdevice 302 may be externally energized and/or recharged or may have itsown energy source 320. The parameters of the modulation signal 400, suchas the frequency, amplitude, duty cycle, pulse width, pulse shape, etc.,can be programmable, non-programmable, modifiable, locally or remotelyupdateable, or others. An external communication device may modify thepulse generator programming to improve treatment.

In addition, or as an alternative to some of the devices to implementthe modulation unit for producing the electrical voltage/current profileof the stimulating, blocking and/or modulating impulse to theelectrodes, the device disclosed in US Patent Application PublicationNo. US2005/0216062, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein, may beemployed. That patent publication discloses a multifunctional electricalstimulation (ES) system adapted to yield output signals for effectingelectromagnetic or other forms of electrical stimulation for a broadspectrum of different biological and biomedical applications, whichproduce an electric field pulse in order to non-invasively stimulatenerves. The system includes an ES signal stage having a selector coupledto a plurality of different signal generators, each producing a signalhaving a distinct shape, such as a sine wave, a square or a saw-toothwave, or simple or complex pulse, the parameters of which are adjustablein regard to amplitude, duration, repetition rate and other variables.Examples of the signals that may be generated by such a system aredescribed in a publication by LIBOFF [A. R. LIBOFF. Signal shapes inelectromagnetic therapies: a primer. pp. 17-37 in: BioelectromagneticMedicine (Paul J. Rosch and Marko S. Markov, eds.). New York: MarcelDekker (2004), the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein]. The signalfrom the selected generator in the ES stage is fed to at least oneoutput stage where it is processed to produce a high or low voltage orcurrent output of a desired polarity whereby the output stage is capableof yielding an electrical stimulation signal appropriate for itsintended application. Also included in the system is a measuring stagewhich measures and displays the electrical stimulation signal operatingon the substance being treated, as well as the outputs of varioussensors which sense prevailing conditions prevailing in this substance,whereby the user of the system can manually adjust the signal, or haveit automatically adjusted by feedback, to provide an electricalstimulation signal of whatever type the user wishes, who can thenobserve the effect of this signal on a substance being treated.

The stimulating and/or modulating impulse signal 410 preferably has afrequency, an amplitude, a duty cycle, a pulse width, a pulse shape,etc. selected to influence the therapeutic result, namely, stimulatingand/or modulating some or all of the transmission of the selected nerve.For example, the frequency may be about 1 Hz or greater, such as betweenabout 15 Hz to 100 Hz, preferably between about 15-50 Hz and morepreferably between about 15-35 Hz. In some embodiments, the frequency is25 Hz. The modulation signal may have a pulse width selected toinfluence the therapeutic result, such as about 1 microseconds to about1000 microseconds, preferably about 100-400 microseconds and morepreferably about 200-400 microseconds. For example, the electric fieldinduced or produced by the device within tissue in the vicinity of anerve may be about 5 to 600 V/m, preferably less than 100 V/m, and evenmore preferably less than 30 V/m. The gradient of the electric field maybe greater than 2 V/m/mm. More generally, the stimulation deviceproduces an electric field in the vicinity of the nerve that issufficient to cause the nerve to depolarize and reach a threshold foraction potential propagation, which is approximately 8 V/m at 1000 Hz.The modulation signal may have a peak voltage amplitude selected toinfluence the therapeutic result, such as about 0.2 volts or greater,such as about 0.2 volts to about 40 volts, preferably between about 1-20volts and more preferably between about 2-12 volts.

In an exemplary embodiment, the waveform comprises bursts of sinusoidalpulses, as shown in FIGS. 2B and 2C. As seen there, individualsinusoidal pulses have a period of T, and a burst consists of N suchpulses. This is followed by a period with no signal (the inter-burstperiod). The pattern of a burst followed by silent inter-burst periodrepeats itself with a period of T. For example, the sinusoidal period Tmay be between about 50-1000 microseconds with a frequency of about 1-20kHz), preferably between about 100-400 microseconds with a frequency ofabout 2.5-10 kHz, more preferably about 133-400 microseconds with afrequency of about 2.5-7.5 kHz and even more preferably about 200microseconds with a frequency of about 5 kHz; the number of pulses perburst may be N=1-20, preferably about 2-10 and more preferably about 5;and the whole pattern of burst followed by silent inter-burst period mayhave a period T comparable to about 5-100 Hz, preferably about 15-50 Hz,more preferably about 25-35 Hz and even more preferably about 25 Hz (amuch smaller value of T is shown in FIG. 2B to make the burstsdiscernable). When these exemplary values are used for T and T, thewaveform contains significant Fourier components at higher frequencies (1/200 microseconds=5000/sec), as compared with those contained intranscutaneous nerve stimulation waveforms, as currently practiced.

The above waveform is essentially a 1-20 kHz signal that includes burstsof pulses with each burst having a frequency of about 5-100 Hz and eachpulse having a frequency of about 1-20 kHz. Another way of thinkingabout the waveform is that it is a 1-20 kHz waveform that repeats itselfat a frequency of about 5-100 Hz.

In some embodiments, an objective of some of the disclosed stimulatorsis to provide both nerve fiber selectivity and spatial selectivity.Spatial selectivity may be achieved in part through the design of theelectrode (or magnetic coil) configuration, and nerve fiber selectivitymay be achieved in part through the design of the stimulus waveform, butdesigns for the two types of selectivity are intertwined. This isbecause, for example, a waveform may selectively stimulate only one oftwo nerves whether they lie close to one another or not, obviating theneed to focus the stimulating signal onto only one of the nerves [GRILLW and Mortimer J T. Stimulus waveforms for selective neural stimulation.IEEE Eng. Med. Biol. 14 (1995): 375-385, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein]. These methods complement others that are used to achieveselective nerve stimulation, such as the use of local anesthetic,application of pressure, inducement of ischemia, cooling, use ofultrasound, graded increases in stimulus intensity, exploiting theabsolute refractory period of axons, and the application of stimulusblocks [John E. SWETT and Charles M. Bourassa. Electrical stimulation ofperipheral nerve. In: Electrical Stimulation Research Techniques,Michael M. Patterson and Raymond P. Kesner, eds. Academic Press. (NewYork, 1981) pp. 243-295, the disclosure of which is incorporated hereinby reference for all purposes as if copied and pasted herein].

For some devices, to date, some of the selection of stimulation waveformparameters for nerve stimulation has been highly empirical, in which theparameters are varied about some initially successful set of parameters,in an effort to find an improved set of parameters for each patient. Amore efficient approach to selecting stimulation parameters might be toselect a stimulation waveform that mimics electrical activity in theanatomical regions that one is attempting stimulate indirectly, in aneffort to entrain the naturally occurring electrical waveform, assuggested in patent number U.S. Pat. No. 6,234,953, entitledElectrotherapy device using low frequency magnetic pulses, to THOMAS etal; the disclosure of which is incorporated herein by reference for allpurposes as if copied and pasted herein, and application numberUS20090299435, entitled Systems and methods for enhancing or affectingneural stimulation efficiency and/or efficacy, to GLINER et al, thedisclosure of which is incorporated herein by reference for all purposesas if copied and pasted herein. One may also vary stimulation parametersiteratively, in search of an optimal setting [U.S. Pat. No. 7,869,885,entitled Threshold optimization for tissue stimulation therapy, toBEGNAUD et al, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein]. However,some stimulation waveforms, such as those described herein, arediscovered by trial and error, and then deliberately improved upon.

Invasive nerve stimulation typically uses square wave pulse signals.However, Applicant found that square waveforms are not ideal fornon-invasive stimulation, as they produce excessive pain, but still canbe used. Prepulses and similar waveform modifications have beensuggested as methods to improve selectivity of nerve stimulationwaveforms, but Applicant also did not find them ideal, although theystill can be used [Aleksandra VUCKOVIC, Marco Tosato and Johannes JStruijk. A comparative study of three techniques for diameter selectivefiber activation in the vagal nerve: anodal block, depolarizingprepulses and slowly rising pulses. J. Neural Eng. 5 (2008): 275-286,the disclosure of which is incorporated herein by reference for allpurposes as if copied and pasted herein; Aleksandra VUCKOVIC, Nico J. M.Rijkhoff, and Johannes J. Struijk. Different Pulse Shapes to ObtainSmall Fiber Selective Activation by Anodal Blocking—A Simulation Study.IEEE Transactions on Biomedical Engineering 51(5, 2004):698-706, thedisclosure of which is incorporated herein by reference for all purposesas if copied and pasted herein; Kristian HENNINGS. Selective ElectricalStimulation of Peripheral Nerve Fibers: Accommodation Based Methods.Ph.D. Thesis, Center for Sensory-Motor Interaction, Aalborg University,Aalborg, Denmark, 2004, the disclosure of which is incorporated hereinby reference for all purposes as if copied and pasted herein].

In some embodiments, the use of feedback to generate the modulationsignal 400 may result in a signal that is not periodic, particularly ifthe feedback is produced from sensors that measure naturally occurring,time-varying aperiodic physiological signals from the patient. In fact,the absence of significant fluctuation in naturally occurringphysiological signals from a patient is ordinarily considered to be anindication that the patient is in ill health. This is because apathological control system that regulates the patient's physiologicalvariables may have become trapped around only one of two or morepossible steady states and is therefore unable to respond normally toexternal and internal stresses. Accordingly, even if feedback is notused to generate the modulation signal 400, it may be useful toartificially modulate the signal in an aperiodic fashion, in such a wayas to simulate fluctuations that would occur naturally in a healthyindividual. Thus, the noisy modulation of the stimulation signal maycause a pathological physiological control system to be reset or undergoa non-linear phase transition, through a mechanism known as stochasticresonance [B. SUKI, A. Alencar, M. K. Sujeer, K. R. Lutchen, J. J.Collins, J. S. Andrade, E. P. Ingenito, S. Zapperi, H. E. Stanley,Life-support system benefits from noise, Nature 393 (1998) 127-128, thedisclosure of which is incorporated herein by reference for all purposesas if copied and pasted herein; W Alan C MUTCH, M Ruth Graham, Linda GGirling and John F Brewster. Fractal ventilation enhances respiratorysinus arrhythmia. Respiratory Research 2005, 6:41, pp. 1-9, thedisclosure of which is incorporated herein by reference for all purposesas if copied and pasted herein].

In some embodiments, the modulation signal 400, with or withoutfeedback, will stimulate the selected nerve fibers in such a way thatone or more of the stimulation parameters (e.g., energy, frequency, andothers mentioned herein) are varied by sampling a statisticaldistribution having a mean corresponding to a selected, or to a mostrecent running-averaged value of the parameter, and then setting thevalue of the parameter to the randomly sampled value. The sampledstatistical distributions will comprise Gaussian and 1/f, obtained fromrecorded naturally occurring random time series or by calculatedformula. Parameter values will be so changed periodically, or at timeintervals that are themselves selected randomly by sampling anotherstatistical distribution, having a selected mean and coefficient ofvariation, where the sampled distributions comprise Gaussian andexponential, obtained from recorded naturally occurring random timeseries or by calculated formula.

In some embodiments, some devices, as disclosed herein, are provided ina “pacemaker” type form, in which electrical impulses 410 are generatedto a selected region of the nerve by a stimulator device on anintermittent basis, to create in the patient a lower reactivity of thenerve.

Embodiments of the Stimulators

The electrodes of the some of the devices, as disclosed herein, areapplied to the surface of the neck, or to some other surface of thebody, and are used to deliver electrical energy non-invasively to anerve. Embodiments may differ with regard to the number of electrodesthat are used, the distance between electrodes, and whether disk, ringor other shapes of electrodes are used. In some embodiments, one selectsthe electrode configuration for individual patients, in such a way as tooptimally focus electric fields and currents onto the selected nerve,without generating excessive currents on the surface of the skin.

One embodiment of an electrode-based stimulator is shown in FIG. 3A. Across-sectional view of the stimulator along its long axis is shown inFIG. 3B. As shown, the stimulator (730) comprises two heads (731) and abody (732) that joins them. Each head (731) contains a stimulatingelectrode. The body of the stimulator (732) contains the electroniccomponents and battery (not shown) that are used to generate the signalsthat drive the electrodes, which are located behind the insulating board(733) that is shown in FIG. 3B. However, in other embodiments of theinvention, the electronic components that generate the signals that areapplied to the electrodes may be separate, but connected to theelectrode head (731) using wires. Furthermore, other embodiments of theinvention may contain a single such head or ore than two heads.

Heads of the stimulator (731) are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes or collars, or the stimulator may be held against the patient'sbody by hand. In either case, the level of stimulation energy may beadjusted with a wheel (734) that also serves as an on/off switch. Alight (735) is illuminated when energy is being supplied to thestimulator. An optional cap may be provided to cover each of thestimulator heads (731), to protect the device when not in use, to avoidaccidental stimulation, and to prevent material within the head fromleaking or drying. Thus, in this embodiment of the invention, mechanicaland electronic components of the stimulator (impulse generator, controlunit, and energy source) are compact, portable, and simple to operate.

Details of one embodiment of the stimulator head are shown in FIGS. 3Cand 3D. The electrode head may be assembled from a disc withoutfenestration (743), or alternatively from a snap-on cap that serves as atambour for a dielectric or conducting membrane, or alternatively thehead may have a solid fenestrated head-cup. The electrode may also be ascrew (745). The preferred embodiment of the disc (743) is a solid,ordinarily uniformly conducting disc (e.g., metal such as stainlesssteel), which is possibly flexible in some embodiments. An alternateembodiment of the disc is a non-conducting (e.g., plastic) aperturescreen that permits electrical current to pass through its apertures,e.g., through an array of apertures (fenestration). The electrode (745,also 340 in FIG. 3B) seen in each stimulator head may have the shape ofa screw that is flattened on its tip. Pointing of the tip would make theelectrode more of a point source, such that the equations for theelectrical potential may have a solution corresponding more closely to afar-field approximation. Rounding of the electrode surface or making thesurface with another shape will likewise affect the boundary conditionsthat determine the electric field. Completed assembly of the stimulatorhead is shown in FIG. 3D, which also shows how the head is attached tothe body of the stimulator (747).

If a membrane is used, it ordinarily serves as the interface shown as351 in FIG. 3B. For example, the membrane may be made of a dielectric(non-conducting) material, such as a thin sheet of Mylar(biaxially-oriented polyethylene terephthalate, also known as BoPET). Inother embodiments, it may be made of conducting material, such as asheet of Tecophlic material from Lubrizol Corporation, 29400 LakelandBoulevard, Wickliffe, Ohio 44092. In one embodiment, apertures of thedisc may be open, or they may be plugged with conducting material, forexample, KM10T hydrogel from Katecho Inc., 4020 Gannett Ave., Des MoinesIowa 50321. If the apertures are so-plugged, and the membrane is made ofconducting material, the membrane becomes optional, and the plug servesas the interface 351 shown in FIG. 2B.

The head-cup (744) may be filled with conducting material (350 in FIG. 1), for example, SIGNAGEL Electrode Gel from Parker Laboratories, Inc.,286 Eldridge Rd., Fairfield N.J. 07004. The head-cup (744) and body ofthe stimulator are made of a non-conducting material, such asacrylonitrile butadiene styrene. The depth of the head-cup from its topsurface to the electrode may be between one and six centimeters. Thehead-cup may have a different curvature than what is shown in FIG. 3D,or it may be tubular or conical or have some other inner surfacegeometry that will affect the Neumann boundary conditions that determinethe electric field strength.

In certain embodiments, the disc interface 743 actually functions as theelectrode and the screw 745 is simply the output connection to thesignal generator electronics. In this embodiment, electricallyconductive fluid or gel is positioned between the signal generator andthe interface or electrode 745. In this embodiment, the conductive fluidfilters out or eliminates high frequency components from the signal tosmooth out the signal before it reaches the electrode(s) 745. When thesignal is generated, energy switching and electrical noise typically addunwanted high frequency spikes back into the signal. In addition, thepulsing of the sinusoidal bursts may induce high frequency components inthe signal. By filtering the signal just before it reaches theelectrodes 745 with the conductive fluid, a smoother, cleaner signal isapplied to the patient, thereby reducing the pain and discomfort felt bythe patient and allowing a higher amplitude to be applied to thepatient. This allows a sufficiently strong signal to be applied to reacha deeper nerve, such as the vagus nerve, without causing too much painand discomfort to the patient at the surface of their skin.

In other embodiments, a low-pass filter may be used instead of theelectrically conductive fluid to filter out the undesirable highfrequency components of the signal. The low-pass filter may comprise adigital or analog filter or simply a capacitor placed in series betweenthe signal generator and the electrode/interface.

If an outer membrane is used and is made of conducting materials, andthe disc (743) in FIG. 3C is made of solid conducting materials such asstainless steel, then the membrane becomes optional, in which case thedisc may serve as the interface 351 shown in FIG. 1 . Thus, anembodiment without the membrane is shown in FIGS. 3C and 3D. Thisversion of the device comprises a solid (but possibly flexible in someembodiments) conducting disc that cannot absorb fluid, thenon-conducting stimulator head (744) into or onto which the disc isplaced, and the electrode (745), which is also a screw. It is understoodthat the disc (743) may have an anisotropic material or electricalstructure, for example, wherein a disc of stainless steel has a grain,such that the grain of the disc should be rotated about its location onthe stimulator head, in order to achieve optimal electrical stimulationof the patient. As seen in FIG. 3D, these items are assembled to becomea sealed stimulator head that is attached to the body of the stimulator(747). The disc (743) may screw into the stimulator head (744), it maybe attached to the head with adhesive, or it may be attached by othermethods that are known in the art. The chamber of the stimulatorhead-cup is filled with a conducting gel, fluid, or paste, and becausethe disc (743) and electrode (745) are tightly sealed against thestimulator head-cup (744), the conducting material within the stimulatorhead cannot leak out. In addition, this feature allows the user toeasily clean the outer surface of the device (e.g., with isopropylalcohol or similar disinfectant), avoiding potential contaminationduring subsequent uses of the device.

In some embodiments, the interface comprises a fluid permeable materialthat allows for passage of current through the permeable portions of thematerial. In these embodiments, a conductive medium (such as a gel) ispreferably situated between the electrode(s) and the permeableinterface. The conductive medium provides a conductive pathway forelectrons to pass through the permeable interface to the outer surfaceof the interface and to the patient's skin.

In other embodiments of the present invention, the interface is madefrom a very thin material with a high dielectric constant, such asmaterial used to make capacitors. For example, it may be Mylar having asubmicron thickness (preferably in the range about 0.5 to about 1.5microns) having a dielectric constant of about 3. Because one side ofMylar is slick, and the other side is microscopically rough, the presentinvention contemplates two different configurations: one in which theslick side is oriented towards the patient's skin, and the other inwhich the rough side is so-oriented. Thus, at stimulation Fourierfrequencies of several kilohertz or greater, the dielectric interfacewill capacitively couple the signal through itself, because it will havean impedance comparable to that of the skin. Thus, the dielectricinterface will isolate the stimulator's electrode from the tissue, yetallow current to pass. In one embodiment of the present invention,non-invasive electrical stimulation of a nerve is accomplishedessentially substantially capacitively, which reduces the amount ofohmic stimulation, thereby reducing the sensation the patient feels onthe tissue surface. This would correspond to a situation, for example,in which at least 30%, preferably at least 50%, of the energystimulating the nerve comes from capacitive coupling through thestimulator interface, rather than from ohmic coupling. In other words, asubstantial portion (e.g., 50%) of the voltage drop is across thedielectric interface, while the remaining portion is through the tissue.

In certain exemplary embodiments, the interface and/or its underlyingmechanical support comprise materials that will also provide asubstantial or complete seal of the interior of the device. Thisinhibits any leakage of conducting material, such as gel, from theinterior of the device and also inhibits any fluids from entering thedevice. In addition, this feature allows the user to easily clean thesurface of the dielectric material (e.g., with isopropyl alcohol orsimilar disinfectant), avoiding potential contamination duringsubsequent uses of the device. One such material is a thin sheet ofMylar, supported by a stainless steel disc, as described above.

The selection of the material for the dielectric constant involves atleast two important variables: (1) the thickness of the interface; and(2) the dielectric constant of the material. The thinner the interfaceand/or the higher the dielectric constant of the material, the lower thevoltage drop across the dielectric interface (and thus the lower thedriving voltage required). For example, with Mylar, the thickness couldbe about 0.5 to about 5 microns (preferably about 1 micron) with adielectric constant of about 3. For a piezoelectric material like bariumtitanate or PZT (lead zirconate titanate), the thickness could be about100-400 microns (preferably about 200 microns or 0.2 mm) because thedielectric constant is >1000.

Another embodiment of the electrode-based stimulator is shown in FIG. 5, showing a device in which electrically conducting material isdispensed from the device to the patient's skin. In this embodiment, theinterface (351 in FIG. 2B) is the conducting material itself. FIGS. 5Aand 5B respectively provide top and bottom views of the outer surface ofthe electrical stimulator 50. FIG. 5C provides a bottom view of thestimulator 50, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 4A-4D show a mesh 51 with openings that permit a conducting gel topass from inside of the stimulator to the surface of the patient's skinat the position of nerve or tissue stimulation. Thus, the mesh withopenings 51 is the part of the stimulator that is applied to the skin ofthe patient, through which conducting material may be dispensed. In anygiven stimulator, the distance between the two mesh openings 51 in FIG.4A is constant, but it is understood that different stimulators may bebuilt with different inter-mesh distances, in order to accommodate theanatomy and physiology of individual patients. Alternatively, theinter-mesh distance may be made variable as in the eyepieces of a pairof binoculars. A covering cap (not shown) is also provided to fit snuglyover the top of the stimulator housing and the mesh openings 51, inorder to keep the housing's conducting medium from leaking or dryingwhen the device is not in use.

FIGS. 4C and 4D show the bottom of the self-contained stimulator 50. Anon/off switch 52 is attached through a port 54, and an energy-levelcontroller 53 is attached through another port 54. The switch isconnected to a battery energy source (320 in FIG. 1 ), and theenergy-level controller is attached to the control unit (330 in FIG. 1 )of the device. The energy source battery and energy-level controller, aswell as the impulse generator (310 in FIG. 1 ) are located (but notshown) in the rear compartment 55 of the housing of the stimulator 50.

Individual wires (not shown) connect the impulse generator 310 to thestimulator's electrodes 56. The two electrodes 56 are shown here to beelliptical metal discs situated between the head compartment 57 and rearcompartment 55 of the stimulator 50. A partition 58 separates each ofthe two head compartments 57 from one another and from the single rearcompartment 55. Each partition 58 also holds its corresponding electrodein place. However, each electrode 56 may be removed to add electricallyconducting gel 350 to each head compartment 57. An optionalnon-conducting variable-aperture iris diaphragm may be placed in frontof each of the electrodes within the head compartment 57, in order tovary the effective surface area of each of the electrodes. Eachpartition 58 may also slide towards the head of the device in order todispense conducting gel through the mesh apertures 51. The position ofeach partition 58 therefore determines the distance 59 between itselectrode 56 and mesh openings 51, which is variable in order to obtainthe optimally uniform current density through the mesh openings 51. Theoutside housing of the stimulator 50, as well as each head compartment57 housing and its partition 58, are made of electrically insulatingmaterial, such as acrylonitrile butadiene styrene, so that the two headcompartments are electrically insulated from one another. Although theembodiment in FIG. 4 is shown to be a non-capacitive stimulator, it isunderstood that it may be converted into a capacitive stimulator byreplacing the mesh openings 51 with a dielectric material, such as asheet of Mylar, or by covering the mesh openings 51 with a sheet of suchdielectric material.

In preferred embodiments of the electrode-based stimulator shown in FIG.4 , electrodes are made of a metal, such as stainless steel, platinum,or a platinum-iridium alloy. However, in other embodiments, theelectrodes may have many other sizes and shapes, and they may be made ofother materials [Thierry KELLER and Andreas Kuhn. Electrodes fortranscutaneous (surface) electrical stimulation. Journal of AutomaticControl, University of Belgrade, 18(2, 2008):35-45; G. M. LYONS, G. E.Leane, M. Clarke-Moloney, J. V. O'Brien, P. A. Grace. An investigationof the effect of electrode size and electrode location on comfort duringstimulation of the gastrocnemius muscle. Medical Engineering & Physics26 (2004) 873-878; Bonnie J. FORRESTER and Jerrold S. Petrofsky. Effectof Electrode Size, Shape, and Placement During Electrical Stimulation.The Journal of Applied Research 4, (2, 2004): 346-354; Gad ALON, GideonKantor and Henry S. Ho. Effects of Electrode Size on Basic ExcitatoryResponses and on Selected Stimulus Parameters. Journal of Orthopaedicand Sports Physical Therapy. 20(1, 1994):29-35].

For example, the stimulator's conducting materials may be nonmagnetic,and the stimulator may be connected to the impulse generator by longnonmagnetic wires (345 in FIG. 2B), so that the stimulator may be usedin the vicinity of a strong magnetic field, possibly with added magneticshielding. As another example, there may be more than two electrodes;the electrodes may comprise multiple concentric rings; and theelectrodes may be disc-shaped or have a non-planar geometry. They may bemade of other metals or resistive materials such as silicon-rubberimpregnated with carbon that have different conductive properties[Stuart F. COGAN. Neural Stimulation and Recording Electrodes. Annu.Rev. Biomed. Eng. 2008. 10:275-309; Michael F. NOLAN. Conductivedifferences in electrodes used with transcutaneous electrical nervestimulation devices. Physical Therapy 71(1991):746-751].

The electrode-based stimulator designs shown in FIGS. 3 and 4 situatethe electrode remotely from the surface of the skin within a chamber.Such a chamber design had been used prior to the availability offlexible, flat, disposable electrodes [U.S. Pat. No. 3,659,614, entitledAdjustable headband carrying electrodes for electrically stimulating thefacial and mandibular nerves, to Jankelson; U.S. Pat. No. 3,590,810,entitled Biomedical body electrode, to Kopecky; U.S. Pat. No. 3,279,468,entitled Electrotherapeutic facial mask apparatus, to Le Vine; U.S. Pat.No. 6,757,556, entitled Electrode sensor, to Gopinathan et al; U.S. Pat.No. 4,383,529, entitled Iontophoretic electrode device, method and gelinsert, to Webster; U.S. Pat. No. 4,220,159, entitled Electrode, toFrancis et al. U.S. Pat. Nos. 3,862,633, 4,182,346, and 3,973,557,entitled Electrode, to Allison et al; U.S. Pat. No. 4,215,696, entitledBiomedical electrode with pressurized skin contact, to Bremer et al; andU.S. Pat. No. 4,166,457, entitled Fluid self-sealing bioelectrode, toJacobsen et al.] The stimulator designs shown in FIGS. 4 and 5 are alsoself-contained units, housing the electrodes, signal electronics, andenergy supply. Portable stimulators are also known in the art, forexample, U.S. Pat. No. 7,171,266, entitled Electro-acupuncture devicewith stimulation electrode assembly, to Gruzdowich. One of the noveltiesof the designs shown in FIGS. 3 and 4 is that the stimulator, along witha correspondingly suitable stimulation waveform, shapes the electricfield, producing a selective physiological response by stimulating thatnerve, but avoiding substantial stimulation of nerves and tissue otherthan the target nerve, particularly avoiding the stimulation of nervesthat produce pain. The shaping of the electric field is described interms of the corresponding field equations in commonly assignedapplication US20210230938 (application Ser. No. 13/075,746) entitledDevices and methods for non-invasive electrical stimulation and theiruse for vagal nerve stimulation on the neck of a patient, to SIMON etal., which is hereby incorporated by reference.

As seen in FIG. 4D, a mesh 531 has openings that permit a conducting gelwithin 351 to pass from the inside of the stimulator to the surface ofthe patient's skin at the location of nerve or tissue stimulation. Thus,the mesh with openings 531 is the part of the magnetic stimulator thatis applied to the skin of the patient.

Another embodiment of an electrode-based stimulator is shown in FIGS.5A-5C. As shown, the stimulator comprises a smartphone (31) with itsback cover removed and joined to a housing (32) that comprises a pair ofelectrode surfaces (33) along with circuitry to control and energy theelectrodes and interconnect with the smartphone. The electrode surface(33) in FIGS. 5A-5C corresponds to item 351 in FIG. 1 . FIG. 5A showsthe side of the smartphone (31) with a touch-screen. FIG. 5B shows thehousing of the stimulator (32) joined to the back of the smartphone.Portions of the housing lie flush with the back of the smartphone, withwindows to accommodate smartphone components that are found on theoriginal back of the smartphone. Such components may also be used withthe stimulator, e.g., the smartphone's rear camera (34), flash (35) andspeaker (36). Other original components of the smartphone may also beused, such as the audio headset jack socket (37) and multi-purpose jack(38). Note that the original components of the smartphone shown in FIG.5 correspond to a Samsung Galaxy smartphone, and their locations may bedifferent for embodiments that use different smartphone models bydifferent smartphone manufacturers. Note that tablets can be used aswell.

FIG. 5C shows that several portions of the housing (32) protrude towardsthe back. The two electrode surfaces (33) protrude so that they may beapplied to the skin of the patient. The stimulator may be held in placeby straps or frames or collars, or the stimulator may be held againstthe patient's body by hand. In some embodiments, the neurostimulator maycomprise a single such electrode surface or more than two electrodesurfaces.

A dome (39) also protrudes from the housing, so as to allow the deviceto lie more or less flat on a table when supported also by the electrodesurfaces. The dome also accommodates a relatively tall component thatmay lie underneath it, such as a battery. Alternatively, the stimulationdevice may be energised by the smartphone's battery. If the batteryunder the dome is rechargeable, the dome may contain a socket (41)through which the battery is recharged using a jack that is insertedinto it, which is, for example, attached to a energy cable from a basestation (described below). The belly (40) of the housing protrudes to alesser extent than the electrodes and dome. The belly accommodates aprinted circuit board that contains electronic components within thehousing (not shown), as described below.

Electronics and Software of the Stimulator

In some embodiments, the signal waveform (FIG. 2 ) that is to be appliedto electrodes of the stimulator is initially generated in a component ofthe impulse generator 310 that is exterior to, and remote from, themobile phone housing. The mobile phone preferably includes a softwareapplication that can be downloaded (e.g., mobile app store, USB cable,memory stick, Bluetooth connection) into the phone to receive, from theexternal control component, a wirelessly transmitted waveform, or toreceive a waveform that is transmitted by cable, e.g., via themulti-purpose jack 38 in FIG. 5 . If the waveforms are transmitted incompressed form, they are preferably compressed in a lossless manner,e.g., making use of FLAC (Free Lossless Audio Codec). Alternatively, thedownloaded software application may itself be coded to generate aparticular waveform that is to be applied to the electrodes (340 in FIG.1C) and subsequently conveyed to the external interface of the electrodeassembly (351 in FIG. 1C and 33 in FIG. 5 ). In some embodiments, thesoftware application is not downloaded from outside the device, but isinstead available internally, for example, within read-only-memory thatis present within the housing of the stimulator (32 in FIGS. 3B and 3C).

In some embodiments, the waveform is first conveyed by the softwareapplication to contacts within the phone's speaker output or theearphone jack socket (37 in FIG. 3B), as though the waveform signal werea generic audio waveform. That pseudo-audio waveform will generally be astereo waveform, representing signals that are to be applied to the“left” and “right” electrodes. The waveform will then be conveyed to thehousing of the stimulator (32 in FIGS. 3B and 3C), as follows. Thehousing of the stimulator may have an attached dangling audio jack thatis plugged into the speaker output or the earphone jack socket 37whenever electrical stimulation is to be performed, or the electricalconnection between the contacts of the speaker output or the earphonejack socket and the housing of the stimulator may be hard-wired. Ineither case, electrical circuits on a printed circuit board locatedunder the belly of the housing (40 in FIG. 3C) of the stimulator maythen shape, filter, and/or amplify the pseudo-audio signal that isreceived via the speaker output or earphone jack socket. An energyamplifier within the housing of the stimulator may then drive the signalonto the electrodes, in a fashion that is analogous to the use of anaudio energy amplifier to drive loudspeakers. Alternatively, the signalprocessing and amplification may be implemented in a separate devicethat can be plugged into sockets on the phone and/or housing of thestimulator (32 in FIGS. 3B and 3C), to couple the software applicationand the electrodes.

In addition to passing the stimulation waveform from the smartphone tothe stimulator housing as described herein, the smartphone may also passcontrol signals to the stimulator housing. Thus, the stimulationwaveform may generally be regarded as a type of analog, pseudo-audiosignal, but if the signal contains a signature series of pulsessignifying that a digital control signal is about to be sent, logiccircuitry in the stimulator housing may then be set to decode the seriesof digital pulses that follows the signature series of pulses, analogousto the operation of a modem.

Many of the steps that direct the waveform to the electrodes, includingsteps that may be controlled by the user via the touchscreen (31 in FIG.3A), are implemented in the above-mentioned software application. By wayof example, the software application may be written for a phone thatuses the Android operating system. Such applications are typicallydeveloped in the Java programming language using the Android SoftwareDevelopment Kit (SDK), in an integrated development environment (IDE),such as Eclipse [Mike WOLFSON. Android Developer Tools Essentials.Sebastopol, Calif.: O'Reilly Media Inc., 2013; Ronan SCHWARZ, PhilDuston, James Steele, and Nelson To. The Android Developer's Cookbook.Building Applications with the Android SDK, Second Edition. Upper SaddleRiver, N.J.: Addison-Wesley, 2013, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein; Shane CONDER and Lauren Darcey. Android WirelessApplication Development, Second Edition. Upper Saddle River, N.J.:Addison-Wesley, 2011; Jerome F. DIMARZIO. Android—A Programmer's Guide.New York: McGraw-Hill. 2008. pp. 1-319, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein]. Application programming interfaces (APIs) that areparticularly relevant to the audio features of such an Android softwareapplication (e.g., MediaPlayer APIs) are described by: Android OpenSource Project of the Open Handset Alliance. Media Playback, at webdomain developer.android.com with subdomain/guide/topics/media/, Jul.18, 2014, the disclosure of which is incorporated herein by referencefor all purposes as if copied and pasted herein. Those APIs can berelevant to a use of the smartphone camera capabilities, as describedbelow. Additional components of the software application are availablefrom device manufacturers [Samsung Mobile SDK, at web domaindeveloper.samsung.com with subdomain/samsung-mobile-sdk, Jul. 18, 2014,the disclosure of which is incorporated herein by reference for allpurposes as if copied and pasted herein].

In some embodiments, the stimulator and/or smartphone will include auser control, such as a switch or button, that disables/enables thestimulator. Preferably, the switch will automatically disable some,many, most, or all smartphone functions when the stimulator is enabled(and vice versa). This ensures that the medical device functionality ofthe smartphone is completely segregated from the rest of the phone'sfunctionality. In some embodiments, the switch will bepassword-controlled such that only the patient/owner of thestimulator/phone will be able to enable the stimulator functionality. Inone such embodiment, the switch will be controlled by a biometric scan(e.g., fingerprint, optical scan or the like) such that the stimulatorfunctionality can only be used by the patient. This ensures that onlythe patient will be able to use the prescribed therapy in the event thephone is lost or stolen.

The stimulator and/or phone can also include software that allows thepatient to order more therapy doses over the internet (discussed in moredetail below in connection with the docking station). The purchase ofsuch therapy doses will require physician authorization through aprescription or the like. To that end, the software can include anauthorization code for entry in order for the patient to downloadauthorization for more therapies. In some embodiments, without suchauthorization, the stimulator will be disabled and will not delivertherapy.

Although the device shown in FIG. 5 is an adapted commercially availablesmartphone, it is understood that in some embodiments, the housing ofthe stimulator may also be joined to and/or energized by a wirelessdevice that is not a phone (e.g., Wi-Fi enabled device, wearable,tablet). Alternatively, the stimulator may be coupled to a phone orother Wi-Fi enabled device through a wireless connection for exchangingdata at short distances, such as Bluetooth or the like. In thisembodiment, the stimulator housing is not attached to the smartphoneand, therefore, may comprise a variety of other shapes and sizes thatare convenient for the patient to carry in his or her purse, wallet orpocket.

In some embodiments, the stimulator housing may be designed as part of aprotective or decorative case for the phone that can be attached to thephone, similar to standard phone cases. In one such embodiment, thestimulator/case may also include additional battery life for the phoneand may include an electrical connection to the phone's battery torecharge the battery (e.g., part of a Mophie® or the like). Thiselectrical connection may also be used to couple the smartphone to thestimulator.

Embodiments with Distributed Controllers

In some embodiments, significant portions of the control of the vagusnerve stimulation reside in controller components that are physicallyseparate from the housing of the stimulator. In these embodiment,separate components of the controller and stimulator housing generallycommunicate with one another wirelessly, although wired or waveguidecommunication is possible. Thus, the use of wireless technology avoidsthe inconvenience and distance limitations of interconnecting cables.Additional reasons in the present disclosure for physically separatingmany components of the controller from the stimulator housing are asfollows.

First, the stimulator may be constructed with the minimum number ofcomponents needed to generate the stimulation pulses, with the remainingcomponents placed in parts of the controller that reside outside thestimulator housing, resulting in a lighter and smaller stimulatorhousing. In fact, the stimulator housing may be made so small that itcould be difficult to place, on the stimulator housing's exterior,switches and knobs that are large enough to be operated easily. Instead,for the present disclosure, the user may generally operate the deviceusing the smartphone touchscreen.

Second, the controller 330 may be given additional functions when freefrom the limitation of being situated within or near the stimulatorhousing. For example, one may add to the controller a data loggingcomponent that records when and how stimulation has been applied to thepatient, for purposes of medical recordkeeping and billing. The completeelectronic medical record database for the patient may be located farfrom the stimulator (e.g., somewhere on the internet), and the billingsystem for the stimulation services that are provided may also beelsewhere, so it would be useful to integrate the controller into thatrecordkeeping and billing system, using a communication system thatincludes access to the internet or telephone networks.

Third, communication from the databases to the controller would also beuseful for purposes of metering electrical stimulation of the patient,when the stimulation is self-administered. For example, if theprescription for the patient only permits only a specified amount ofstimulation energy to be delivered during a single session of vagusnerve stimulation, followed by a wait-time before allowing the nextstimulation, the controller can query the database and then permit thestimulation only when the prescribed wait-time has passed. Similarly,the controller can query the billing system to assure that the patient'saccount is in order, and withhold the stimulation if there is a problemwith the account.

Fourth, as a corollary of the previous considerations, the controllermay be constructed to include a computer program separate from thestimulating device, in which the databases are accessed via cell phoneor internet connections.

Fifth, in some applications, it may be desired that the stimulatorhousing and parts of the controller be physically separate. For example,when the patient is a child, one wants to make it impossible for thechild to control or adjust the vagus nerve stimulation. The bestarrangement in that case is for the stimulator housing to have notouchscreen elements, control switches or adjustment knobs that could beactivated by the child. Alternatively, any touchscreen elements,switches and knobs on the stimulator can be disabled, and control of thestimulation then resides only in a remote controller with a child-proofoperation, which would be maintained under the control of a parent orhealthcare provider.

Sixth, in some applications, the particular control signal that istransmitted to the stimulator by the controller will depend onphysiological and environmental signals that are themselves transmittedto and analyzed by the controller. In such applications, many of thephysiological and environmental signals may already be transmittedwirelessly, in which case it is most convenient to design an externalpart of the controller as the hub of all such wireless activity,including any wireless signals that are sent to and from the stimulatorhousing.

With these considerations in mind, an embodiment of can include a basestation 332 (FIG. 6 ) that may send/receive data to/from the stimulator,and may send/receive data to/from databases and other components of thesystem, including those that are accessible via the internet (or anothernetwork such as local area, wide area, satellite, cellular). Typically,the base station will be a laptop computer attached to additionalcomponents needed for it to accomplish its function. Thus, prior to anyparticular stimulation session, the base station may load into thestimulator parameters of the session, including waveform parameters, orthe actual waveform.

In some embodiments, the base station is also used to limit the amountof stimulation energy that may be consumed by the patient during thesession, by charging the stimulator's rechargeable battery with only aspecified amount of releasable electrical energy, which is differentthan setting a parameter to restrict the duration of a stimulationsession. Thus, the base station may comprise a energy supply that may beconnected to the stimulator's rechargeable battery, and the base stationmeters the recharge. As a practical matter, the stimulator may thereforeuse two batteries, one for applying stimulation energy to the electrodes(the charge of which may be limited by the base station) and the otherfor performing other functions. Methods for evaluating a battery'scharge or releasable energy can be as disclosed in U.S. Pat. No.7,751,891, entitled Energy supply monitoring for an implantable device,to ARMSTRONG et al, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein.Alternatively, some control components within the stimulator housing maymonitor the amount of electrode stimulation energy that has beenconsumed during a stimulation session and stop the stimulation sessionwhen a limit has been reached, irrespective of the time when the limithas been reached.

The communication connections between different components of thestimulator's controller are shown in FIG. 6 , which is an expandedrepresentation of the control unit 330 in FIG. 1 . Connection betweenthe base station controller components 332 and components within thestimulator housing 331 is denoted in FIG. 6 as 334. Connection betweenthe base station controller components 332 and internet-based (ornetwork based) or smartphone components 333 is denoted as 335.Connection between the components within the stimulator housing 331 andinternet-based or smartphone components 333 is denoted as 336. Forexample, control connections between the smartphone and stimulatorhousing via the audio jack socket would fall under this category, aswould any wireless communication directly between the stimulator housingitself and a device situated on the internet. In principle, theconnections 334, 335 and 336 in FIG. 6 may be either wired or wirelessor waveguide-based. Different embodiments may lack one or more of theconnections.

Although infrared or ultrasound wireless control might be used tocommunicate between components of the controller, they are not preferredbecause of line-of-sight limitations. Instead, in the presentdisclosure, the communication between devices preferably makes use ofradio communication within unlicensed ISM frequency bands (260-470 MHz,902-928 MHz, 2400-2.4835 GHz). Components of the radio frequency systemin devices in 331, 332, and 333 typically comprise a system-on-chiptransceiver with an integrated microcontroller; a crystal; associatedbalun & matching circuitry, and an antenna [Dag GRINI. RF Basics, RF forNon-RF Engineers. Texas Instruments, Post Office Box 655303, Dallas,Tex. 75265, 2006, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein].

Transceivers based on 2.4 GHz offer high data rates (greater than 1Mbps) and a smaller antenna than those operating at lower frequencies,which makes them suitable for with short-range devices. Furthermore, a2.4 GHz wireless standard (e.g., Bluetooth, Wi-Fi, and ZigBee) may beused as the protocol for transmission between devices. Although theZigBee wireless standard operates at 2.4 GHz in most jurisdictionsworldwide, it also operates in the ISM frequencies 868 MHz in Europe,and 915 MHz in the USA and Australia. Data transmission rates vary from20 to 250 kilobits/second with that standard. Because many commerciallyavailable health-related sensors may operate using ZigBee, its use maybe recommended for applications in which the controller uses feedbackand feedforward methods to adjust the patient's vagus nerve stimulationbased on the sensors' values, as described below in connection with FIG.11 [ZigBee Wireless Sensor Applications for Health, Wellness andFitness. ZigBee Alliance 2400 Camino Ramon Suite 375 San Ramon, Calif.94583].

A 2.4 GHz radio has higher energy consumption than radios operating atlower frequencies, due to reduced circuit efficiencies. Furthermore, the2.4 GHz spectrum is crowded and subject to significant interference frommicrowave ovens, cordless phones, 802.11b/g wireless local areanetworks, Bluetooth devices, etc. Sub-GHz radios enable lower energyconsumption and can operate for years on a single battery. Thesefactors, combined with lower system cost, make sub-GHz transceiversideal for low data rate applications that need maximum range andmulti-year operating life.

The antenna length needed for operating at different frequencies is 17.3cm at 433 MHz, 8.2 cm at 915 MHz, and 3 cm at 2.4 GHz. Therefore, unlessthe antenna is included in a neck collar that supports the device shownin FIG. 3 , the antenna length may be a disadvantage for 433 MHztransmission. The 2.4 GHz band has the advantage of enabling one deviceto serve in all major markets worldwide since the 2.4 GHz band is aglobal spectrum standard. However, 433 MHz is a viable alternative to2.4 GHz for most of the world, and designs based on 868 and 915 MHzradios can serve the US and European markets with a single product.

Range is determined by the sensitivity of the transceiver and its outputenergy. A primary factor affecting radio sensitivity is the data rate.Higher data rates reduce sensitivity, leading to a need for higheroutput energy to achieve sufficient range. For many applications thatrequire only a low data rate, the preferred rate is 40 Kbps where thetransceiver can still use a standard off-the-shelf 20 parts per millioncrystal.

A signal waveform that might be transmitted wirelessly to the stimulatorhousing was shown in FIGS. 2B and 2C. As seen there, individualsinusoidal pulses have a period of tau, and a burst consists of N suchpulses. This is followed by a period with no signal (the inter-burstperiod). The pattern of a burst followed by silent inter-burst periodrepeats itself with a period of T. For example, the sinusoidal periodtau may be 200 microseconds; the number of pulses per burst may be N=5;and the whole pattern of burst followed by silent inter-burst period mayhave a period of T=40000 microseconds, which is comparable to 25 Hzstimulation (a much smaller value of T is shown in FIG. 2C to make thebursts discernable). When these exemplary values are used for T and tau,the waveform contains significant Fourier components at higherfrequencies ( 1/200 microseconds=5000/sec). Such a signal may be easilytransmitted using 40 Kbps radio transmission. Compression of the signalis also possible, by transmitting only the signal parameters tau, N, T,Emax, etc., but in that case the stimulator housing's controlelectronics would then have to construct the waveform from thetransmitted parameters, which would add to the complexity of componentsof the stimulator housing.

However, because it is contemplated that sensors attached to thestimulator housing may also be transmitting information, the datatransfer requirements may be substantially greater than what is requiredonly to transmit the signal shown in FIG. 2 . Therefore, the presentdisclosure may make use of any frequency band, not limited to the ISMfrequency bands, as well as techniques known in the art to suppress oravoid noise and interferences in radio transmission, such as frequencyhopping and direct sequence spread spectrum.

Applications of Stimulators to the Patient

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retropharyngeal spaceon each side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

Of course, it will be recognized that the vagus nerve may be stimulatedthrough other mechanisms. For example, auricular vagal nerve stimulationinvolves stimulation of the auricular branch of the vagus nerve, oftentermed the Alderman's nerve or Arnold's nerve. This nerve may bestimulated through the transcutaneous systems and methods describedherein by transmitting electrical impulses through the outer skinsurface of the patient's ear to the auricular branch of the vagus nerve.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra shows an embodimentof a location of a stimulation as “Vagus Nerve Stimulation,” relative toits connections with other anatomical structures that are potentiallyaffected by the stimulation. In some embodiments, various brain andbrainstem structures are modulated by the stimulation. These structuresare described in sections of the disclosure that follow, along with somerationale for modulating their activity as a prevention, prophylaxis,diagnosis, monitoring, amelioration, or treatment of various medicalconditions, diseases or disorders.

FIG. 7 illustrates use of the device 50 to stimulate the vagus nerve atthat location in the neck, in which the stimulator device 50 is shown tobe applied to the target location on the patient's neck as describedherein. For reference, FIG. 7 shows the locations of the followingvertebrae: first cervical vertebra 71, the fifth cervical vertebra 75,the sixth cervical vertebra 76, and the seventh cervical vertebra 77.

FIG. 8 shows the stimulator 30 applied to the neck of a child, which ispartially immobilized with a foam cervical collar 78 that is similar toones used for neck injuries and neck pain. The collar is tightened witha strap 79, and the stimulator is inserted through a hole in the collarto reach the child's neck surface. In such applications, the stimulatormay be turned on and off remotely, using a wireless controller that maybe used to adjust the stimulation parameters of the controller (e.g.,on/off, stimulation amplitude, frequency, etc.).

FIG. 9 provides a more detailed view of use of the electrical stimulator30, when positioned to stimulate the vagus nerve at the neck location.The anatomy shown in FIG. 9 is a cross-section of half of the neck atvertebra level C6. The vagus nerve 60 is identified in FIG. 9 , alongwith the carotid sheath 61 that is identified there in bold peripheraloutline. The carotid sheath encloses not only the vagus nerve, but alsothe internal jugular vein 62 and the common carotid artery 63.Structures that may be identified near the surface of the neck includethe external jugular vein 64 and the sternocleidomastoid muscle 65,which protrudes when the patient turns his or her head. Additionalorgans in the vicinity of the vagus nerve include the trachea 66,thyroid gland 67, esophagus 68, scalenus anterior muscle 69, scalenusmedius muscle 70, levator scapulae muscle 71, splenius colli muscle 72,semispinalis capitis muscle 73, semispinalis colli muscle 74, longuscolli muscle and longus capitis muscle 75. The sixth cervical vertebra76 is shown with bony structure indicated by hatching marks. Additionalstructures shown in the figure are the phrenic nerve 77, sympatheticganglion 78, brachial plexus 79, vertebral artery and vein 80,prevertebral fascia 81, platysma muscle 82, omohyoid muscle 83, anteriorjugular vein 84, sternohyoid muscle 85, sternothyroid muscle 86, andskin with associated fat 87.

Stimulation may be performed on the left or right vagus nerve or on bothof them simultaneously and alternately. The position and angularorientation of the device are adjusted about that location until thepatient perceives stimulation when current is passed through thestimulator electrodes. The applied current is increased gradually, firstto a level wherein the patient feels sensation from the stimulation. Theenergy is then increased, but is set to a level that is less than one atwhich the patient first indicates any discomfort. Straps, harnesses, orframes may be used to maintain the stimulator in position. Thestimulator signal may have a frequency and other parameters that areselected to produce a therapeutic result in the patient, i.e.,stimulation parameters for each patient are adjusted on anindividualized basis. Ordinarily, the amplitude of the stimulationsignal is set to the maximum that is comfortable for the patient, andthen the other stimulation parameters are adjusted.

The stimulation is then performed with a sinusoidal burst waveform likethat shown in FIG. 2 . As seen there, individual sinusoidal pulses havea period of T, and a burst consists of N such pulses. This is followedby a period with no signal (the inter-burst period). The pattern of aburst followed by silent inter-burst period repeats itself with a periodof T. For example, the sinusoidal period T may be between about 50-1000microseconds and a frequency of about 1-20 kHz, preferably between about100-400 microseconds and a frequency of about 2.5-10 kHz, morepreferably about 133-400 microseconds and a frequency of about 2.5-7.5kHz and even more preferably about 200 microseconds and a frequency ofabout 5 kHz; the number of pulses per burst may be N=1-20, preferablyabout 2-10 and more preferably about 5; and the whole pattern of burstfollowed by silent inter-burst period may have a period T comparable toabout 5-100 Hz, preferably about 15-50 Hz, more preferably about 25-35Hz and even more preferably about 25 Hz (a much smaller value of T isshown in FIG. 2C to make the bursts discernable). When these examplevalues are used for T and T, the waveform contains significant Fouriercomponents at higher frequencies ( 1/200 microseconds=5000/sec), ascompared with those contained in transcutaneous nerve stimulationwaveforms.

When a patient is using the stimulation device to performself-stimulation therapy, e.g., at home or at a workplace, he or shewill follow the steps that are now described. It is assumed that theoptimal stimulation position has already been marked on the patient'sneck, as described above and that a reference image of the fluorescentspots has already been acquired. The previous stimulation session willordinarily have discharged the rechargeable batteries of the stimulatorhousing, and between sessions, the base station will have been used torecharge the stimulator at most only up to a minimum level. If thestimulator's batteries had charge remaining from the previousstimulation session, the base station will discharge the stimulator to aminimum level that will not support stimulation of the patient.

The patient can initiate the stimulation session using the mobile phoneor base station (e.g., laptop computer) by invoking a computer program(on the laptop computer or through an app on the mobile phone) that isdesigned to initiate use of the stimulator. The programs in thesmartphone and base station may initiate and interact with one anotherwirelessly, so in what follows, reference to the program (app) in thesmartphone may also apply to the program in the base station, becauseboth may be operating in tandem. For security reasons, the program wouldbegin with the request for a user name and a password, and that user'sdemographic information and any data from previous stimulatorexperiences would already be associated with it in the login account.The smartphone may also be used to authenticate the patient using afingerprint or voice recognition app, or other reliable authenticationmethods. If the patient's physician has not authorized furthertreatments, the base station will not charge the stimulator's batteries,and instead, the computer program will call or otherwise communicatewith the physician's computer requesting authorization. Afterauthorization by the physician is received, the computer program (on thelaptop computer or through an app on the mobile phone) may also query adatabase that is ordinarily located somewhere on the internet to verifythat the patient's account is in order. If it is not in order, theprogram may then request prepayment for one or more stimulationsessions, which would be paid by the patient using a credit card, debitcard, PayPal, cryptocurrency, bitcoin, or the like. The computer programwill also query its internal database or that of the base station todetermine that sufficient time has elapsed between when the stimulatorwas last used and the present time, to verify that any requiredwait-time has elapsed.

Having received authorization to perform a nerve stimulation session,the patient interface computer program will then ask the patientquestions that are relevant to the selection of parameters that the basestation will use to make the stimulator ready for the stimulationsession. The questions that the computer program asks are dependent onthe condition for which the patient is being treated, which for presentpurposes is considered to be treatment for an autoimmune disease ordisorder. The questions may be things like (1) is this an acute orprophylactic treatment? (2) if acute, then how severe is your pain andin what locations, how long have you had it, (3) has anything unusual ornoteworthy occurred since the last stimulation? etc.

Having received such preliminary information from the patient, thecomputer programs will perform instrument diagnostic tests and make thestimulator ready for the stimulation session. In general, the algorithmfor setting the stimulator parameters will have been decided by thephysician and will include the extent to which the stimulator batteriesshould be charged, which the vagus nerve should be stimulated (right orleft), and the time that the patient should wait after the stimulationsession is ended until initiation of a subsequent stimulation session.The computer will query the physician's computer to ascertain whetherthere have been any updates to the algorithm, and if not, will use theexisting algorithm. The patient will also be advised of the stimulationsession parameter values by the interface computer program, so as toknow what to expect.

Once the base station has been used to charge the stimulator's batteriesto the requisite charge, the computer program (or smartphone app) willindicate to the patient that the stimulator is ready for use. At thatpoint, the patient would clean the electrode surfaces, and make anyother preliminary adjustments to the hardware. The stimulationparameters for the session will be displayed, and any options that thepatient is allowed to select may be made. Once the patient is ready tobegin, he or she will press a “start” button on the touchscreen and maybegin the vagus nerve stimulation.

Multiple methods may be used to test whether the patient is properlyattempting to stimulate the vagus nerve (or another nerve or organ ormuscle or bone) on the intended side of the neck (or another portion ofa human body). For example, accelerometers and gyroscopes within thesmartphone may be used to determine the position and orientation of thesmartphone's touch screen relative to the patient's expected view of thescreen, and a decision by the stimulator's computer program as to whichhand is being used to hold the stimulator may be made by measuringcapacitance on the outside of the stimulator body, which may distinguishfingers wrapped around the device versus the ball of a thumb [RaphaelWIMMER and Sebastian Boring. HandSense: discriminating different ways ofgrasping and holding a tangible user interface. Proceedings of the 3rdInternational Conference on Tangible and Embedded Interaction, pp.359-362. ACM New York, N.Y., 2009, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein]. Pressing of the electrodes against the skin will resultin a resistance drop across the electrodes, which can initiate operationof the rear camera. A fluorescent image should appear on the smartphonescreen only if the device is applied to the side of the neck in thevicinity of the fluorescent spots that had been applied as a tattooearlier. If the totality of these data indicates to the computer programthat the patient is attempting to stimulate the wrong vagus nerve orthat the device is being held improperly, the stimulation will bewithheld, and the stimulator may then communicate with the patient viathe interface computer program (in the mobile phone or laptop computer)to alert the patient of that fact. The program may then offersuggestions on how to better apply the device to the neck.

However, if the stimulator is being properly applied, and an image ofthe fluorescent spots on the patient's neck appears on the screen of thephone, the stimulator begins to stimulate according to predeterminedinitial stimulus parameters. The patient will then adjust the positionand angular orientation of the stimulator about what he or she thinks isthe correct neck position, until he or she perceives stimulation whencurrent is passed through the stimulator electrodes. An attempt is alsomade to superimpose the currently viewed fluorescence image of the neckspots with the previously acquired reference image. The applied currentis increased gradually using keys on the keyboard of the base station oron the smartphone touchscreen, first to a level wherein the patientfeels sensation from the stimulation. The stimulation amplitude is thenincreased by the patient, but is set to a level that is less than one atwhich he first senses any discomfort. By trial and error, thestimulation is then optimized by the patient, who tries to find thegreatest acceptable sensation with the lowest acceptable stimulationamplitude, with the stimulator aligned using the fluorescent spots. Ifthe stimulator is being held in place by hand, it is likely that theremay be inadvertent fluctuating movement of the stimulator, due forexample to neck movement during respiration. Such relative movementswill affect the effectiveness of the stimulation. However, they may bemonitored by accelerometers and gyroscopes within the smartphone, whichmay be transmitted as movement data from the stimulator to the patientinterface computer program (in the mobile phone or laptop computer). Therelative movements may also be monitored and measured as fluctuations inthe position of the fluorescence spots that are being imaged. Bywatching a graphical display of the relative movements shown by thepatient interface computer program, the patient may use that display inan attempt to deliberately minimize the movements. Otherwise, thepatient may attempt to adjust the amplitude of the stimulator ascompensation for movement of the stimulator away from its optimumposition. In a section that follows, it is described how the stimulatoritself may modulate the amplitude of the stimulation in order to makesuch compensations.

During the session, the patient may lift the stimulator from his neck,which will be detected as an increase in resistance between theelectrodes and a loss of the fluorescent image of the spots on thepatient's neck. When that occurs, the device will withhold energy to thestimulator for reasons of safety. The patient can then reapply thestimulator to his neck to resume the session, although the interruptionof stimulation will be recognized and recorded by the computer program.Stimulation by the patient will then continue until the battery of thestimulator is depleted, or the patient decides to terminate thestimulation session. At that point, the patient will acknowledge thatthe stimulation session is finished by touching a response button on thesmartphone screen, whereupon the stimulator will transfer to the basestation data that its microprocessor has caused to be stored regardingthe stimulation session (e.g., stimulation amplitude as a function oftime and information about movements of the device during the session,duration of the stimulation, the existence of interruptions, etc.). Suchinformation will then be transmitted to and displayed by the patientinterface computer program (in the mobile phone or laptop computer),which will subsequently ask the patient questions regarding theeffectiveness of the stimulation. Such questions may be in regard to thepost-stimulation severity of the headache, whether the severitydecreased gradually or abruptly during the course of the stimulation,and whether anything unusual or noteworthy occurred during thestimulation. Some, most, many, or all of such post-stimulation data willalso be delivered over the internet by the patient interface computerprogram to the physician's computer for review and possible adjustmentof the algorithm that is used to select stimulation parameters andregimens. It is understood that the physician will adjust the algorithmbased not only on the experience of each individual patient, but on theexperience of all patients collectively so as to improve effectivenessof the stimulator's use, for example, by identifying characteristics ofmost and least responsive patients.

Before logging off of the interface computer program, the patient mayalso review database records and summaries about all previous treatmentsessions, so as to make his or her own judgment about treatmentprogress. If the stimulation was part of a prophylactic treatmentregimen that was prescribed by the patient's physician, the patientinterface computer program will remind the patient about the schedulefor the upcoming self-treatment sessions and allow for a rescheduling ifnecessary.

For some patients, the stimulation may be performed for as little as 60seconds, but it may also be for up to 30 minutes or longer. Thetreatment is generally performed once or twice daily or several times aweek, for 12 weeks or longer before a decision is made as to whether tocontinue the treatment. For patients experiencing intermittent symptoms,the treatment may be performed only when the patient is symptomatic.However, it is understood that parameters of the stimulation protocolmay be varied in response to heterogeneity in the pathophysiology ofpatients. Different stimulation parameters may also be used as thecourse of the patient's condition changes.

In some embodiments, pairing of vagus nerve stimulation may be with anadditional sensory stimulation. The paired sensory stimulation may bebright light, sound, tactile stimulation, or electrical stimulation ofthe tongue to simulate odor/taste, e.g., pulsating with the samefrequency as the vagus nerve electrical stimulation. The rationale forpaired sensory stimulation is the same as simultaneous, pairedstimulation of both left and right vagus nerves, namely, that the pairof signals interacting with one another in the brain may result in theformation of larger and more coherent neural ensembles than the neuralensembles associated with the individual signals, thereby enhancing thetherapeutic effect. This pairing may be considered especially when somesuch corresponding sensory circuit of the brain is thought to be partlyresponsible for triggering the migraine headache.

In some embodiments, various methods can use vagal nerve stimulation tosuppress inflammation. In some embodiments, some methods and devicesinvolve the inhibition of pro-inflammatory cytokines, or morespecifically, stimulation of the vagus nerve to inhibit and/or block therelease of such pro-inflammatory cytokines. In some embodiments, somemethods and devices use vagal nerve stimulation to increase theconcentration or effectiveness of anti-inflammatory cytokines. TRACEY etal do not consider the modulation of anti-inflammatory cytokines to bepart of the cholinergic anti-inflammatory pathway that their method ofvagal nerve stimulation is intended to activate. Thus, they explain that“activation of vagus nerve cholinergic signaling inhibits TNF (tumornecrosis factor) and other proinflammatory cytokine overproductionthrough ‘immune’ a7 nicotinic receptor-mediated mechanisms” [V. A.PAVLOV and K. J. Tracey. Controlling inflammation: the cholinergicanti-inflammatory pathway. Biochemical Society Transactions 34, (2006,6): 1037-1040, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein]. In contrast,anti-inflammatory cytokines are said to be part of a different“diffusible anti-inflammatory network, which includes glucocorticoids,anti-inflammatory cytokines, and other humoral mediators” [CZURA C J,Tracey K J. Autonomic neural regulation of immunity. J Intern Med.257(2005, 2): 156-66, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein]. Others makea similar distinction between vagal and humoral mediation [GUYON A,Massa F, Rovere C, Nahon J L. How cytokines can influence the brain: arole for chemokines? J Neuroimmunol 2008; 198:46-55, the disclosure ofwhich is incorporated herein by reference for all purposes as if copiedand pasted herein].

The disclaiming by TRACEY and colleagues of a role for anti-inflammatorycytokines as mediators of inflammation following stimulation of thevagus nerve may be due to a recognition that anti-inflammatory cytokines(e.g., TGF-ß) are usually produced constitutively, whilepro-inflammatory cytokines (e.g., TNF-alpha) are not producedconstitutively, but are instead induced. However, anti-inflammatorycytokines are inducible as well as constitutive, so that for example, anincrease in the concentrations of potentially anti-inflammatorycytokines such as transforming growth factor-beta (TGF-ß) can in fact beaccomplished through stimulation of the vagus nerve [RA BAUMGARTNER, V ADeramo and M A Beaven. Constitutive and inducible mechanisms forsynthesis and release of cytokines in immune cell lines. The Journal ofImmunology 157 (1996, 9): 4087-4093, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein; CORCORAN, Ciaran; Connor, Thomas J; O'Keane, Veronica;Garland, Malcolm R. The effects of vagus nerve stimulation on pro- andanti-inflammatory cytokines in humans: a preliminary report.Neuroimmunomodulation 12 (5, 2005): 307-309, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein].

An example of a pro-anti-inflammatory mechanism that is particularlyrelevant to the treatment of multiple sclerosis is as follows. TGF-ßconverts undifferentiated T cells into regulatory T (Treg) cells thatblock the autoimmunity that causes demyelination in multiple sclerosis.However, in the presence of interleukin-6, TGF-ß also causes thedifferentiation of T lymphocytes into proinflammatory IL-17cytokine-producing T helper 17 (TH17) cells, which promote autoimmunityand inflammation. Thus, it is conceivable that an increase of TGF-ßlevels might actually cause or exacerbate inflammation, rather thansuppress it. Accordingly, a step in an embodiment of the methods thatare disclosed herein is to deter TGF-ß from realizing itspro-inflammatory potential, by selecting nerve stimulation parametersthat bias the potential of TGF-ß towards anti-inflammation, and/or bytreating the patient with an agent such as the vitamin A metaboliteretinoic acid that is known to promote such an anti-inflammatory bias[MUCIDA D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, CheroutreH. Reciprocal TH17 and regulatory T cell differentiation mediated byretinoic acid. Science 317(2007, 5835): 256-60, the disclosure of whichis incorporated herein by reference for all purposes as if copied andpasted herein; Sheng XIAO, Hulin Jin, Thomas Korn, Sue M. Liu, MohamedOukka, Bing Lim, and Vijay K. Kuchroo. Retinoic acid increases Foxp3+regulatory T cells and inhibits development of Th17 cells by enhancingTGF-ß-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptorexpression. J Immunol. 181(2008, 4): 2277-2284, the disclosure of whichis incorporated herein by reference for all purposes as if copied andpasted herein]. Retinoic acid is a member of a class of compounds knownas retinoids, comprising three generations: (1) retinol, retinal,retinoic acid (tretinoin, Retin-A), isotretinoin and alitretinoin; (2)etretinate and acitretin; (3) tazarotene, bexarotene and Adapalene.

In some embodiments, endogenous retinoic acid that is released byneurons themselves is used to produce the anti-inflammatory bias. Thus,vagal nerve stimulation may induce differentiation through release ofretinoic acid that is produced in neurons from retinaldehyde byretinaldehyde dehydrogenases, and some embodiments disclosed herein canpromote anti-inflammatory regulatory T cell (Treg) differentiation bythis type of mechanism [van de PAVERT S A, Olivier B J, Goverse G,Vondenhoff M F, Greuter M, Beke P, Kusser K, Höpken U E, Lipp M,Niederreither K, Blomhoff R, Sitnik K, Agace W W, Randall T D, de JongeW J, Mebius R E. Chemokine CXCL13 is essential for lymph node initiationand is induced by retinoic acid and neuronal stimulation. Nat Immunol.10(11, 2009): 1193-1199, the disclosure of which is incorporated hereinby reference for all purposes as if copied and pasted herein].

The retinoic acid so released might also directly inhibit the release orfunctioning of proinflammatory cytokines, which would be ananti-pro-inflammatory mechanism that is distinct from the one proposedby TRACEY and colleagues [Malcolm Maden. Retinoic acid in thedevelopment, regeneration and maintenance of the nervous system. NatureReviews Neuroscience 8(2007), 755-765, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein]. However, if the proinflammatory cytokine that is blockedis TNF-alpha, its inhibition in multiple sclerosis patients might becounterproductive. This is because blocking TNF-alpha with the druglenercept promotes and exacerbates multiple sclerosis attacks ratherthan delaying them, which might be attributable to the fact thatTNF-alpha promotes remyelination and the proliferation ofoligodendrocytes that perform the myelination. [ANONYMOUS. TNFneutralization in MS: Results of a randomized, placebo controlledmulticenter study. Neurology 1999, 53:457, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein; ARNETT H A, Mason J, Marino M, Suzuki K, Matsushima G K,Ting J P. TNF alpha promotes proliferation of oligodendrocyteprogenitors and remyelination. Nat Neurosci 2001, 4:1116-1122, thedisclosure of which is incorporated herein by reference for all purposesas if copied and pasted herein].

In this example, the competence of anti-inflammatory cytokines may bemodulated by the retinoic acid (RA) signaling system of the nervoussystem. The most important mechanism of RA activity is the regulation ofgene expression. This is accomplished by its binding to nuclear retinoidreceptors that are ligand-activated transcription factors. Thus, RA actsas a transcriptional activator for a large number of other, downstreamregulatory molecules, including enzymes, transcription factors,cytokines, and cytokine receptors. Retinoic acid is an essentialmorphogen in vertebrate development and participates in tissueregeneration in the adult [Jorg M E Y and Peter MdCaffery. Retinoic AcidSignaling in the Nervous System of Adult Vertebrates. The Neuroscientist10(5, 2004): 409-421, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein]. RA alsoincreases synaptic strength in a homeostatic response (synaptic scaling)to neuronal inactivity through a mechanism involving protein synthesisthat requires the participation of TNF-alpha. RA is also intimatelyinvolved in the control of the rhythmic electrical activity of thebrain. More generally, all-trans retinoic acid, 9-cis retinoic acid, and13-cis retinoic acid are some of a very small number of entrainmentfactors that regulate the natural rhythmicity of metabolic processes inmany types of individual cells [Mehdi Tafti, Norbert B. Ghyselinck.Functional Implication of the Vitamin A Signaling Pathway in the Brain.Arch Neurol. 64(12, 2007): 1706-1711, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein].

The potentially anti-inflammatory cytokine TGF-beta is a member of theTGF-beta superfamily of neurotrophic factors. Neurotrophic factors serveas growth factors for the development, maintenance, repair, and survivalof specific neuronal populations, acting via retrograde signaling fromtarget neurons by paracrine and autocrine mechanisms. Other neurotrophicfactors also promote the survival of neurons during neurodegeneration.These include members of the nerve growth factor (NGF) superfamily, theglial-cell-line-derived neurotrophic factor (GDNF) family, the neurokinesuperfamily, and non-neuronal growth factors such as the insulin-likegrowth factors (IGF) family. However, major problems in using suchneurotrophic factors for therapy are their inability to cross theblood-brain-barrier, adverse effects resulting from binding to thereceptor in other organs of the body and their low diffusion rate[Yossef S. Levy, Yossi Gilgun-Sherki, Eldad Melamed and Daniel Offen.Therapeutic Potential of Neurotrophic Factors in NeurodegenerativeDiseases. Biodrugs 2005; 19 (2): 97-127, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein].

It is known that vagal nerve stimulation and transcranial magneticstimulation can increase the levels of at least one neurotrophic factorin the brain, namely, brain-derived neurotrophic factor (BDNF) in theNGF superfamily, which has been studied extensively in connection withthe treatment of depression. However, vagal nerve stimulation toincrease levels of neurotrophic factors has not been reported inconnection with neurodegenerative diseases. Because BDNF may bemodulated by stimulating the vagus nerve, vagal nerve stimulation maylikewise promote the expression of other neurotrophic factors inpatients with neurodegenerative disease, thereby circumventing theproblem of blood-brain barrier blockage [Follesa P, Biggio F, Gorini G,Caria S, Talani G, Dazzi L, Puligheddu M, Marrosu F, Biggio G. Vagusnerve stimulation increases norepinephrine concentration and the geneexpression of BDNF and bFGF in the rat brain. Brain Research 1179(2007):28-34, the disclosure of which is incorporated herein by reference forall purposes as if copied and pasted herein; Biggio F, Gorini G, UtzeriC, Olla P, Marrosu F, Mocchetti I, Follesa P. Chronic vagus nervestimulation induces neuronal plasticity in the rat hippocampus. Int JNeuropsychopharmacol. 12(9, 2009):1209-21, the disclosure of which isincorporated herein by reference for all purposes as if copied andpasted herein; Roberta Zanardini, Anna Gazzoli, Mariacarla Ventriglia,Jorge Perez, Stefano Bignotti, Paolo Maria Rossini, Massimo Gennarelli,Luisella Bocchio-Chiavetto. Effect of repetitive transcranial magneticstimulation on serum brain derived neurotrophic factor in drug resistantdepressed patients. Journal of Affective Disorders 91 (2006) 83-86, thedisclosure of which is incorporated herein by reference for all purposesas if copied and pasted herein]. US Patent Application PublicationUS20100280562, the disclosure of which is incorporated herein byreference for all purposes as if copied and pasted herein, entitledBiomarkers for monitoring treatment of neuropsychiatric diseases, to PIet al, disclosed the measurement of GDNF and other neurotrophic factorsfollowing vagal nerve stimulation. However, that application isconcerned with the search for biomarkers involving the levels of GDNF,rather than a method for treating autoimmune diseases using vagal nervestimulation.

FIG. 10 illustrates mechanisms or pathways through which stimulation ofthe vagus nerve may be used to reduce inflammation in patients. In whatfollows, it is understood that not all of the pathways or mechanisms maybe used in the treatment of a particular patient and that pathways ormechanisms that are not shown in FIG. 10 may also be used. Thus,particular pathways or mechanisms are invoked by the selection ofparticular stimulation parameters, such as current, frequency, pulsewidth, duty cycle, etc. Nevertheless, as an aid to understanding theapplications that follow, it is useful to consider at once all themechanisms shown in FIG. 10 .

Two types of pathways are shown in FIG. 10 . The pathways that stimulateor upregulate are indicated with an arrow ( ). The pathways that inhibitor downregulate are indicated with a blockage bar ( ). Pathwaysresulting from stimulation of the vagus nerve are shown to stimulateretinoic acid 81, anti-inflammatory cytokines 82 such as TGF-beta, andneurotrophic factors 83 such as BDNF. The patient may also be treatedwith retinoic acid or some other retinoid by administering it as a drug84. For cytokines that may have both anti-inflammatory andpro-inflammatory capabilities, the retinoic acid biases such cytokinesto exhibit their anti-inflammatory potential, as shown in the pathwaylabeled as 85. Pro-inflammatory cytokines, on the other hand, promoteinflammation by pathways labeled as 86. Stimulation of the vagus nerveinhibits the release of pro-inflammatory cytokines 91 directly throughpathways that have been described by TRACEY and colleagues. The otherpathways shown in FIG. 8 to inhibit inflammation following stimulationof the vagus nerve are novel to this disclosure, and include inhibitionof inflammation via anti-inflammatory cytokine pathways 92 includingthose that inhibit the release of pro-inflammatory cytokines 93,inhibition via neurotrophic factors 94 including those that inhibit therelease of pro-inflammatory cytokines 95, and inhibition via retinoicacid pathways 96 including those that inhibit the release ofpro-inflammatory cytokines 97.

It is understood that the labels in FIG. 10 that are used for simplicityto describe the pathways actually refer to a large set of relatedpathways. For example, the box labeled as “retinoic acid” actuallyrefers to not only retinoic acid but also to a larger class ofretinoids, as well as to retinaldehyde dehydrogenases, retinoic acidreceptors (RAR), retinoid X receptors (RXR), retinoic acid responseelements (RAREs), and more generally to the retinoic acid signalingsystem of the nervous system and related pathways.

Furthermore, it is understood that the box labeled “Anti-InflammatoryCytokine, e.g., TGF-beta” can actually be placed within the box entitled“Neurotrophic Factor”, because TFG-beta is a member of the superfamilyof TGF-beta neurotrophic factors [Yossef S. Levy, Yossi Gilgun-Sherki,Eldad Melamed and Daniel Offen. Therapeutic Potential of NeurotrophicFactors in Neurodegenerative Diseases. Biodrugs 2005; 19 (2): 97-127,the disclosure of which is incorporated herein by reference for allpurposes as if copied and pasted herein]. However, because TGF-beta isordinarily referred to simply as a cytokine, and because itsanti-inflammatory competence is known to be influenced by retinoic acid,it was placed in a separate box to avoid undue confusion.

The role of the sympathetic nervous system (SNS) in the regulation ofthe immune system has been long appreciated through the activity of thehypothalamic pituitary-adrenal axis (HPA) and through whichcorticosteroids (cortisol) and other naturally occurringimmunosuppressive compounds are released (Rook, 1999). In parallel withthis understanding, beginning in the 1930s and 1940s, it was observedthat a splenectomy could provide relief from severe inflammatoryconditions such as Rheumatoid arthritis (Bach, 1946). It was a naturalextension of these two lines of thinking, therefore, to attempt tomodulate the splenic nerve (an element of the SNS) and identify how theimmune system was impacted. The effects of stimulating these neuralinputs to the spleen began to be reported as early as the 1960s (Davieset al., 1968) (FIG. 132.1).

Besedovsky et al. (1979) described the SNS as playing an important rolein a feedback loop that coupled lymphoid organ activity to the CNS. Inthis model, the efferent arm of the SNS projects to immune systemorgans, releasing NE from sympathetic nerve terminals in these organs(Elenkov et al., 2000). The role of NE in modulating macrophages andother immune cells in an anti-inflammatory direction has been wellestablished (Hu et al., 1991). Both endogenous, tonic expression, andvolume transmission through extra synaptic means, i.e., varicosities,have been proposed as a means for maintaining a baseline level ofsuppression over immune activity (Straub et al., 1998). With respect tothe afferent arm of this feedback loop, it has been suggested thatperipheral cytokine levels are able to modulate the CNS to altersympathetic outflow. In fact, two separate groups reported, in 1989 and1991, that infusion of IL-1! or IFN-″ into the ventricles of the braincauses rapid, significant reductions in peripheral and splenic immunecell activity (Sundar et al., 1989; Brown et al., 1991). To facilitatethis activation within the CNS, afferent vagal fibers were proposed as afunctional pathway for peripheral cytokine modulation of the CNS (Maieret al., 1998).

Further evidence of VN involvement with splenic immune function camewhen Bernik et al. (2001) studied the significant peripheral,anti-inflammatory effects of semapimod (a compound formerly known asCNI-1493), which, at one point, was believed to inhibit inflammationthrough inhibition of p38 MAP kinase. Minute quantities of semapimod,were administered intracerebral-ventricular (ICV), just as IL-1 # andIFN-$ had been used previously. However, unlike the prior thesis ofsympathetic pathway involvement, Bernik et al. reversed the assumptionof efferent signaling from sympathetic to the parasympathetic (vagus),when it was found that severing of the VN abolished theanti-inflammatory effects. Their conclusion was that semapimod was apotent activator of efferent, vagal outflow (Oke et al., 2007).Borovikova et al. (2000) had previously demonstrated that electricalstimulation of the distal remains of the severed VN, i.e., the efferentvagal component, was able to trigger anti-inflammatory effects, even inthe absence of ICV administration of semapimod, IL-1 #, or IFN-$. (Aswill be discussed later, additional studies showed that electricalstimulation of the afferent arms, post vagotomy, were also able toaffect the same immune modulation.)

A review of the available literature on this subject strongly suggeststhat there is broad, albeit not universal, agreement that stimulation ofthe VN (using appropriate stimulation, signal parameters) generates asplenic nerve-mediated, anti-inflammatory effect. Initial proposals toexplain the pathway suggest a simple efferent model that is based solelyon acetylcholine release (the primary neurotransmitter released byefferent vagal fibers), whereby direct release of acetylcholine andbinding to receptors on macrophages suppresses the production ofinflammatory cytokines. The specific, efferent pathway was hypothesizedto be through a binding of acetylcholine to the $7-nicotinic,acetylcholine receptor ($7nAChR), since the anti-inflammatory effect ofefferent (post vagotomy) stimulation was lost in $7nAChR knockoutanimals (de Jonge et al., 2007).

In some embodiments, the systemic anti-inflammatory effects of VNS arebelieved to result from the activation of sympathetic fibers in thesplenic nerve, through a connection at the celiac ganglion. Thesesympathetic fibers release norepinephrine into the spleen in closeproximity to a specialized group of immune cells that releaseacetylcholine, or ACh. This release of ACh activates a receptor, thealpha 7 nicotinic ACh receptor, or 7nAChR, on cytokine-releasing immunecells called macrophages. Activation of these receptors is believed tofunction by blocking transcription factors that promote inflammatorycytokine expression. Based on the role of ACh in activating thispathway, which is shown in FIG. 11 below, it has been termed thecholinergic anti-inflammatory pathway, or CAP.

Stimulation of the Vagus Nerve to Treat Conditions

Example 1

A parallel-group randomized controlled trial has been undertaken withthe aim of exploring the feasibility of noninvasive vagal nervestimulation (nVNS) after major colorectal surgery. Forty patientsundergoing colorectal surgery for malignancy were allocated equally toSham and Active stimulation groups. The Active stimulation groupincluded nVNS with the devices and methods described herein. nVNS wasself-administered by the patients bilaterally over the cervical surfacelandmarks for 5 days before and after surgery. Outcomes of interest werepostoperative complications and adverse events measured using theClavien-Dindo scale, treatment compliance, device usability according tothe Systems Usability Scale (SUS) and clinical measures of bowelrecovery.

Safety outcomes included the incidence of complications within 30 daysafter surgery measured using the Clavien-Dindo scale (minor, gradesI-II; major, grades III-V) and the incidence of treatment-relatedadverse events. Each participant was assigned a single gradecorresponding to the highest recorded complication. Clinical outcomeswere days until first flatus, stool and tolerance of solid diet. Thesewere expressed individually and then collapsed into composite measuresof GI-2 (time to first stool and tolerance of solid diet) and GI-3 (timeto first flatus or stool, and tolerance of solid diet). The need fornasogastric tube intubation, parenteral nutrition and postoperativemorphine consumption between days 0 and 3 (expressed as oral morphineequivalent values) were explored descriptively.

In the feasibility population, the most prominent differences in bowelrecovery were time to first flatus (2.35±1.32 vs 1.65±0.88 days) andtime to tolerance of solid diet (2.18±2.21 vs 1.75±0.91 days) in Shamand Active groups, respectively. The time to first stool wasapproximately the same across both groups (4.18±1.85 vs 4.20±1.36 days).When expressed compositely, the time to achieve the GI-3 outcome was2.94±1.98 vs 2.25±0.85 days and the time to achieve the GI-2 outcome was4.53±2.03 vs. 4.25±1.33 days. Overall, a nasogastric tube was requiredin 5/37 (13.5%) participants, including 2/17 (11.8%) in the Sham and3/20 (15.0%) in the Active group. Total parenteral nutrition wasrequired by a single participant in each group. Postoperative morphineconsumption between days 0 and 3 (expressed as oral morphine equivalentvalues) was 139±175 mg and 122±140 mg, respectively. A more completedescription of the results of this study can be found in thepublication: Noninvasive Vagus Nerve Stimulation to Reduce Ileus AfterMajor Colorectal Surgery: Early Development Study; Stephen J. Chapman,Jack A. Helliwell, Maureen Naylor, Cerys Tassinari, Nei Corrigan andDavid G. Jayne; DOI: 10:1111/codi.15561

Example 2

Pre-clinical studies have been conducted in animal models of ischemicstroke. These studies have shown that direct VNS for a period of 1 hour,initiated within 30 min after the onset of transient MCA occlusion(MCAO) in rats led up to 51% reduction in infarct volume in the brain.In addition to that, supporting data from the several different studiessuggest that even up to 72% reduction in infarct size is possible withdirect VNS. Interestingly, unpublished data from the coordinatinginvestigator of the Applicant's current clinical study have confirmedthe protective effect of direct VNS in models of permanent ischemia,embolic MCAO, distal MCAO, and in animals with comorbid conditions whenapplied as late as 3 hours after induction of ischemia. Althoughclinical efficacy of direct VNS is well established in epilepsy anddrug-resistant depression, the need for surgical implantation makesdirect VNS an impractical treatment for widespread application in acutestroke.

In one study conducted by Applicant, nVNS was performed after right MCAOin spontaneously hypertensive rats using a pair of electrodes placed onthe skin between mid to lower portion of the neck. Electricalstimulation (1 msec duration, 5 kHz sine waves repeated at 25 Hz) wasdelivered for 2 minutes at every 10 minutes for a period of 1 hourstarting 30 minutes after induction of MCAO. The animals that receivednVNS developed a significant reduction (33%) in infarct size compared tothe animals that received sham stimulation (control group). Thereduction in infarct volume was associated with improved neurologicalscores and forelimb grip strength measurements at 24 hours post-surgeryin the group that received nVNS compared to control animals. Neitherunilateral nor bilateral stimulation did not cause any systemic andcardiac adverse events.

The optimal dose and therapeutic time window of nVNS was alsoinvestigated in this study. Electrical stimulation of the cervical vagusnerve was initiated 30 minutes, 4 hours, and 5 hours after ischemia andrepeated at every 10 and 15 minutes for a period of 1 hour in differentexperimental groups. The results demonstrated that the favorable effectof nVNS on infarct volume was retained when applied up to 4 hours afterthe induction of ischemia. The protective effect at 4 hours wasassociated with improved neurological score and grip strengthmeasurements at 24 hours. The effect of nVNS on infarct size disappearedwhen treatment was initiated 5 hours after MCAO. These findings suggestthat the therapeutic window of nVNS in rats is 4 hours.

Subsequent studies demonstrated that the protective effect of nVNS didnot differ between stimulations repeated at every 5 minutes and thoserepeated at every 10 minutes. The effect size was smaller but stillsignificant when stimulations were applied at every 15 minutes. Therewas no reduction in infarct size when stimulations were delivered atevery 30 minutes. Since evolution of ischemic injury is much slower inhumans than in rats, in the current study, Applicant has determined thata slightly larger therapeutic time window (6 hours) may be used forhumans to still obtain clinical benefit. This decision to use a 6-hourtime window can be further supported by the evidence showing that twoout of every three stroke patients with proximal arterial occlusionharbor a significant penumbra beyond 9 hours of stroke onset.

The safety and efficacy of nVNS in intracerebral hemorrhage was testedin blood injection- and collagenase injection-induced intracerebralhemorrhage models in rats (unpublished data from the PI). In bothmodels, nVNS caused nonsignificant reduction in hemorrhage volume onpostmortem brain samples obtained 24 hours after the induction ofintracerebral hemorrhage. This effect was accompanied by a slight butnonsignificant improvement in functional outcome in the nVNS treatedanimals. Overall, available evidence indicates that nVNS is not harmfulin intracerebral hemorrhage. The implication of this finding for humanapplication is that nVNS can be administered early after stroke based onclinical diagnosis alone.

Systems of the Present Disclosure

Referring now to FIG. 12 , a system 100 for stimulating a nerve in apatient, such as the vagus nerve, according to the present disclosurewill not be described is a control theory representation of thedisclosed vagus nerve stimulation methods. As shown, system 100 includesa stimulator 210, which may include one or more electrodes 114, a pulsegenerator 116 and an energy source 112. Electrodes 114, pulse generator116 and energy source 112 may all be housed in a single housing, asdescribed in detail above. In an alternative embodiment, electrodes 114are disposed separately from energy source 112 and pulse generator 116.Electrodes 114 may be coupled to these components via wired connectionsor wirelessly. In the latter configuration, electrodes 114 may includesuitable electronic components coupled thereto to receive the electricalimpulse(s) from pulse generator 116 and to apply those electricalimpulse(s) through electrodes 114 to the patient. Such electroniccomponents may include, for example, a wireless receiver or similarcomponent that receives the signal from a wireless transmitter coupledto pulse generator 116.

In still another embodiment, pulse generator 116 and energy source 112are coupled to each other, either wirelessly, via wired connections, ordirectly in a housing that contains both components. This housing may,for example, include a wireless transmitter and may be worn by thepatient in manners known to those skilled in the art, so that the signalcan be transmitted from the housing to electrodes 114.

System 100 further includes a controller 118 that is coupled tostimulator 210 and may be used to select or set parameters for thestimulation protocol (amplitude, frequency, pulse width, burst number,electrode positioning etc.), the treatment regimen discussed above(i.e., duration and number of doses, etc.) or alert the patient as tothe need to use or adjust the stimulator (i.e., an alarm). Controller118 may be directly coupled to stimulator 210 via wired connectors orwithin the same housing, or it may be wirelessly coupled to stimulator210.

Significant portions of the control of the vagus nerve stimulation mayreside in controller components that are physically separate fromstimulator 210. In this embodiment, separate components of thecontroller 118 and stimulator 210 generally communicate with one anotherwirelessly. Thus, the use of wireless technology avoids theinconvenience and distance limitations of interconnecting cables.

In certain embodiments, system 100 may further include a mobile device120 that either couples controller 118 to stimulator 210 or vice versa.Mobile device 120 may comprise a mobile phone, such as a smartphone, asmartwatch, iPad, laptop computer or any other mobile device having acomputing function and wireless transmission technology.

System 100 may further include one or more sensors 122 used fordetecting certain physiological parameters of the patient based on thestimulation of the nerve. The preferred sensors will include onesordinarily used for ambulatory monitoring. For example, the sensors maycomprise those used in conventional Holter and bedside monitoringapplications, for monitoring heart rate and variability, ECG,respiration depth and rate, core temperature, hydration, blood pressure,brain function, oxygenation, skin impedance, and skin temperature. Thesensors may be embedded in garments or placed in sports wristwatches, ascurrently used in programs that monitor the physiological status ofsoldiers [G. A. SHAW, A. M. Siegel, G. Zogbi, and T. P. Opar. Warfighterphysiological and environmental monitoring: a study for the U.S. ArmyResearch Institute in Environmental Medicine and the Soldier SystemsCenter. MIT Lincoln Laboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141].The ECG sensors should be adapted to the automatic extraction andanalysis of particular features of the ECG, for example, indices ofP-wave morphology, as well as heart rate variability indices ofparasympathetic and sympathetic tone. Measurement of respiration usingnoninvasive inductive plethysmography, mercury in silastic strain gaugesor impedance pneumography is particularly advised, in order to accountfor the effects of respiration on the heart. A noninvasive accelerometermay also be included among the ambulatory sensors, in order to identifymotion artifacts. An event marker may also be included in order for thepatient to mark relevant circumstances and sensations.

For brain monitoring, the sensors may comprise ambulatory EEG sensors[CASSON A, Yates D, Smith S, Duncan J, Rodriguez-Villegas E. Wearableelectroencephalography. What is it, why is it needed, and what does itentail? IEEE Eng Med Biol Mag. 29(3, 2010):44-56] or optical topographysystems for mapping prefrontal cortex activation [Atsumori H, Kiguchi M,Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearableoptical topography system for mapping the prefrontal cortex activation.Rev Sci Instrum. 2009 April; 80(4):043704]. Signal processing methods,comprising not only the application of conventional linear filters tothe raw EEG data, but also the nearly real-time extraction of non-linearsignal features from the data, may be considered to be a part of the EEGmonitoring [D. Puthankattil SUBHA, Paul K. Joseph, Rajendra Acharya U,and Choo Min Lim. EEG signal analysis: A survey. J Med Syst34(2010):195-212]. In the present application, the features wouldinclude EEG bands (e.g., delta, theta, alpha, beta).

For any given position of the stimulator relative to the vagus nerve, itis also possible to infer the amplitude of the electric field that itproduces in the vicinity of the vagus nerve. This is done by calculationor by measuring the electric field that is produced by the stimulator asa function of depth and position within a phantom that simulates therelevant bodily tissue [Francis Marion MOORE. Electrical Stimulation forpain suppression: mathematical and physical models. Thesis, School ofEngineering, Cornell University, 2007; Bartosz SAWICKI, Robert Szmurło,Przemystaw Płonecki, Jacek Starzyński, Stanisław Wincenciak, AndrzejRysz. Mathematical Modelling of Vagus Nerve Stimulation. pp. 92-97 in:Krawczyk, A. Electromagnetic Field, Health and Environment: Proceedingsof EHE'07. Amsterdam, IOS Press, 2008]. Thus, in order to compensate formovement, the controller may increase or decrease the amplitude of theoutput from the stimulator (u) in proportion to the inferred deviationof the amplitude of the electric field in the vicinity of the vagusnerve, relative to its desired value.

In some cases, it may be difficult, or impossible for patients to mayreflect self-administer the device, such as immediately after surgeryor, whilst the latter may reflect a lack of motivation once bowelfunction has returned.

Referring now to FIG. 13 , another embodiment of the present disclosureincludes first and second electrodes 102, 104 configured for attachmentto an outer skin surface of the patient, such as the neck. Electrodes102, 104 may include a suitable adhesive that secured them to a skinsurface. Suitable adhesive electrodes for use with the present inventionmay include electrode pads, self-adhesive electrodes or the like.Electrodes 102, 104 may be coupled to pulse generator 116 and/or energysupply 112 via wires or wirelessly. In a preferred embodiment,electrodes 102, 104 will include a wireless receiver and suitableelectronic components (not shown) for receiving a wireless signal frompulse generator 116 to apply an electrical impulse through the outerskin surface of the patient.

In this embodiment, electrodes 102, 104 may be placed in a suitablelocation on the patient's neck and adhered thereto. Electrodes 102, 104receive electrical impulses from pulse generator 116. The duration,amplitude, frequency and treatment paradigm for the electrical impulsesmay be controlled by controller 118, mobile device 120, or via anotherelectronic device coupled to pulse generator 116. This embodimentallows, for example, a physician to secure electrodes 102, 104 to thepatient's neck such that the treatment paradigm may be followed withoutpatient involvement. This is particularly useful for treating patientsthat are unable or unwilling to self-treat. For example, in some cases,patients recovering from surgery, such as major colorectal surgery maybe either incapable of self-treatment, or their compliance with thetreatment protocol may not be complete. In another example, stroke orTIA victims may not have suitable mental faculties for self-treatmentsoon after the onset of the stroke or TIA.

Referring now to FIG. 14A, another embodiment of the present inventioncomprises a stimulator (not shown) that may be secured to the outer skinsurface of the patient's neck. Stimulator may be housed in an outercovering or patch 106 to protect stimulator from the environment. Thepatch 106 may include a suitable adhesive strip or pad on one surfacefor adhering the patch 106 and stimulator to the outer skin surface ofthe patient.

The stimulator in this embodiment includes one or more electrodes. Thestimulator may also include a power source such as a battery, and asignal generator for applying the electrical impulses to the electrodes.Alternatively, the power source and/or the signal generator may bewirelessly coupled to the electrodes, as discussed above. An externalcontroller may be wirelessly coupled to the stimulator to provide astimulation protocol to the signal generator and to control other keyfunctions of the signal, such as power, amplitude, duration frequencyand the like.

The stimulator may reside in a housing that is removably coupled to thepatch via a snap-fitting, Velcro, or other suitable attachment means. Inthis embodiment, the patch may be adhered to the patient and thestimulator may be removed and reattached without removing the patch.This allows the healthcare professions to, for example, recharge thebattery, troubleshoot the device and/or control the stimulation therapyon the device.

The stimulator may also include a conductive fluid, such as a gel pad,disposed between the electrode(s) and the patient's outer skin surfaceto enhance conductivity of the electrical impulses through the outerskin surface to the nerve.

Alternatively, outer covering 106 may comprise any wearable materialthat may include the stimulator. For example, depending on the locationof the target nerve on the patient's body, the stimulator may beattached to, or embedded within, a wearable garment, such as a shirt,scarf, watch, hat, gloves, pants, shoes, boots, socks, underwear, belt,dress, jacket, sweater, ear muffs, or the like. The wearable garment mayalso comprise an accessory, such as a wristband, ankle or wristbracelet, necklace, earrings, a compression garment, an ankle or kneebrace or the like.

In yet another embodiment, the garment itself is the stimulator. Forexample, the garment may comprise an electronic textile or e-textilethat includes fabrics that enable digital components, such aselectrodes, pulse generators, batteries wireless receivers and otherelectronic components to be embedded therein. Electronic textiles aredistinct from wearable garments because the emphasis is placed on theseamless integration of textiles with electronic elements likemicrocontrollers, sensors, and actuators. In one embodiment, theelectronic textile may comprise an organic electronics material that isconducting and has insulated electrical components that allows thegarment to be washed without damaging the electronic components.

The stimulator of this embodiment includes one or more electrodes forapplying electrical impulses to a nerve within the patient, as discussedabove. The electrodes may include a wireless receiver and suitableelectronics to receive the electrical impulses from pulse generator 116.Alternatively, the stimulator may also include pulse generator 116and/or energy supply 112. In this embodiment, the stimulator may be, forexample, wireless coupled to controller 118, mobile device 120 oranother suitable control device.

The stimulator may also include an array of electrodes. The electrodearray may include multiple sets of electrodes with each set ofelectrodes configured to apply electrical impulses through the outerskin surface of the patient, as discussed above. Each of the sets ofelectrodes may be individually coupled to the pulse generator, eitherdirectly, through wires, or wireless as described above. The electrodearray may have multiple patterns. For example, the array may be linear,square, circular or any other suitable shape.

In certain embodiments, the electrode array comprises two or more setsof electrodes, each spaced apart from each other between about 2 mm toabout 25 mm, preferably between about 4 mm to about 10 mm. The electrodearray preferably comprises a shape that substantially corresponds to atarget area of the patient's neck. In one embodiment, the target area isthe area on the neck that allows for electrical impulses to be passedthrough the skin to the vagus nerve (discussed in detail below).

The electrode sets may each be individually coupled to pulse generator116 such that electrical impulses can be applied to all of the electrodesets, some of the electrode sets or only one of the electrode sets.

FIG. 14B illustrates a representative electrode 130 that includes anelectrically conductive surface 132 for contacting the outer skinsurface of the patient. Electrode 130 may further include an adhesivepad 136 for attaching electrode 130 to the outer skin surface, and aninsulating material 134 for electrically isolating conductive surface132.

FIG. 14B illustrates a representative electrode 130 and a representativelead 140 for use with one of the embodiments of the present disclosure.As shown, lead 140 may include a distal connector 142 for coupling toelectrode 130, an insulated electrical wire or other connection 144 anda proximal connector 146 for coupling electrode 130 to a suitable powersource and signal generator (now shown).

In this embodiment, the system may further include one or more sensors122, such as those described above, for detecting whether the nerve hasbeen stimulated, the amplitude of the stimulation, or whether the nervehas been stimulated with sufficient amplitude and other parameters tofire an action potential. The sensors may detect a physiologicalparameter of the patient. Alternatively, the sensors may be coupled tothe electrodes and may sense one or more parameters of the electrodes,such as impedance, amplitude, voltage or the like.

The sensors may also be coupled to the controller 118. In thisembodiment, the controller is configured to receive input from thesensors and to direct the pulse generator 116 to apply electricalimpulses to one or more sets of the electrodes 114 based on this input.For example, the sensors may provide data that suggests that one or moreof the sets of electrodes is not positioned properly to stimulate thenerve, or to stimulate the nerve at the optimal signal strength to causethe nerve to fire an action potential. The controller is configured toshift the electrical impulse to the set or sets of electrodes thatprovide a sufficient electrical impulse to the nerve to cause it to firean action potential. In this manner, the controller can optimize theapplication of the electrical impulses to the nerve.

This embodiment is particularly useful for applying electrical impulsesthrough an outer skin surface of a patient to a deeper nerve, such asthe vagus nerve. The optimal positioning of the electrodes can bechallenging in such an application. If the electrodes are placedincorrectly on the neck, the electrical signals may not pass through tothe nerve, or they may only pass through at limited strength that is notsufficient to cause the nerve to fire an action potential. With thisembodiment, an array of electrodes may be placed over a broader area ofthe outer skin surface. The controller may direct the pulse generator toselectively apply electrical impulses to each set of electrodes. Thesensors will then provide feedback to the controller, as discussedabove, and the controller will determine the optimal set or sets ofelectrodes in which to apply the electrical impulses.

Embodiments of Reusable Neurostimulators

Referring now to FIGS. 15 and 16A-16C, systems and methods for refillingneurostimulator devices, such as the ones portrayed above, will now bedescribed. FIG. 15 illustrates another embodiment of a stimulator device150 according to the present disclosure. Device 150 includes a housing152 for housing the signal generator, energy source and other electroniccomponents described above. Housing 152 includes first and secondelectrodes 154, 156 extending from an upper surface of housing 152.Housing 152 further includes a user input 158 that may, for example,include an energy control that turns the device On/Off and/or a signalcontrol that causes the signal generator to transmit electrical impulsesto the electrodes. Housing 152 may include additional user inputs, suchas controls for amplitude level of the electrical impulses and the like.Housing further includes one or more user displays or icons 160 thatprovide information regarding the operation of the device. For example,user display 160 may illustrate the number of doses that the device hasavailable, as discussed in more detail below. User display may includeadditional information, such as status of the device, a single indicatorthat alerts the patient that the electrodes are not properly positionedagainst an outer skin surface such that current may pass therethrough.

Device 150 may include an accompanying vibration and/or audible signalor buzzer in case the icons are not visible or when the patient isasleep or otherwise not able to view user interface 160. In thisembodiment, inputs 158 may further comprise controls that turn ON/OFFthe vibration or the audible signals (e.g., a mute button).

FIG. 16A shows a schematic diagram of an embodiment of a systemcontaining a medical device and an input device according to thisdisclosure. FIG. 16B shows a schematic diagram of an embodiment of asystem containing a neurostimulator and a reader according to thisdisclosure. FIG. 16C shows a schematic diagram of an embodiment of asystem containing a neurostimulator and a transceiver according to thisdisclosure.

In particular, in FIG. 16A, a system 200A includes a housing 202, aprocessor 204, a memory 206, a medical device 208, and an input device210. The system 200A is energized via an energy source, such as arechargeable or single-use battery, a mains energy line, a photovoltaiccell, a fluid turbine, or others. For example, when the system 200A isenergized via the battery, then the battery can be positioned interioror exterior to the housing 202, yet securely supported via the housing202 (e.g., fastening, mating, interlocking, adhering, hook-and-looping).For example, the battery can be rechargeable, whether over a wired,wireless, or waveguide connection, such as via a wireless charger housedor coupled to the housing 202. Similarly, when the system 200A isenergized via the mains energy line, then the system 200A includes aconductive wire (e.g., copper, aluminum) or a cable (e.g. coaxial, datacommunication) spanning between the housing 202 and the mains energyline, with the conductive wire or the cable being coupled (e.g.,mechanically, electrically) the housing 202, such as via a plug, asocket, a junction box, a pigtail, or others, and the mains energy line,such as via a plug, a socket, a junction box, a pigtail, or others.

The housing 202 houses (e.g., internally, externally) the processor 204,the memory 206, the medical device 208, and the input device 210. Thehousing 202 can include plastic, metal, rubber, or others. The housing202 can be rigid, elastic, resilient, or flexible. For example, thehousing 202 can be included in or embodied as a phone, a tablet, alaptop, a phone/tablet/laptop case, a patch, an adhesive bandage, astrip, an anklet, a belt, a bracelet, a necklace, a garment, a pad, aring, a mattress, a pillow, a blanket, a robot, a surgical instrument, astimulator, an infusion device, or others. For example, the housing 202can be embodied as described in US Patent Application Publication20140330336 and U.S. Pat. Nos. 8,874,205, 9,174,066, 9,205,258,9,375,571, and 9,427,581, all of which are herein incorporated byreference for all purposes as if copied and pasted herein, such as allstructures, all functions, and all methods of manufacture and use, asdisclosed therein. As such, the medical device 208 can be embodied asdescribed in US Patent Application Publication 20140330336 and U.S. Pat.Nos. 8,874,205, 9,174,066, 9,205,258, 9,375,571, and 9,427,581, all ofwhich are herein incorporated by reference for all purposes as if copiedand pasted herein, such as all structures, all functions, and allmethods of manufacture and use, as disclosed therein.

In some embodiments, the housing 202 includes a plurality of housings202, where the processor 204, the memory 206, the medical device 208,and the input device 210 are distributed (e.g., internally, externally)among the housings 202 in any permutational or combinatory manner. Forexample, one of the housings 202 may include the processor 204, thememory 206, whereas another of the housings 202 may include the medicaldevice 208, and the input device 210, where the one of the housings 202and the another of the housings 202 are signally coupled to each other,such as via wiring, wireless, transceivers, waveguides, or others. Forexample, one of the housings 202 may include the processor 204, thememory 206, and the medical device 208, whereas another of the housings202 may include the input device 210, where the one of the housings 202and the another of the housings 202 are signally coupled to each other,such as via wiring, wireless, transceivers, waveguides, or others.

In some embodiments, the housing 202 is anti-tamper or includes ananti-tamper device or technique, such as via a mechanic or chemicaltechnique. Note that anti-tamper or the anti-tamper device includes atleast one of a tamper resistance, a tamper detection, a tamper response,or a tamper evidence. For example, the housing 202 can be mechanicallyanti-tamper via including a screw that can be operated with anon-standard bit. For example, the housing 202 can be chemicallyanti-tamper via including a tamper evident seal.

The processor 204 is coupled to the memory 206, the medical device 208,and the input device 210, such as via wiring, wireless, transceivers,waveguides, or other wireless or wired coupling methods. The processor204 can include a single core or multicore processor. The processor 204can be included in or be a controller, such as a programmable logiccontroller (PLC) or others. The processor 204 can be distinct from themedical device 208 or be a component of the medical device 208.

The memory 206, whether volatile or non-volatile, is at least one of amechanical memory, such as a punch card or others, or a semiconductormemory, such as a flash memory or others. The memory 206 can be distinctfrom the medical device 208 or be a component of the medical device 208.The memory 206 can receive, such as via a physical recordation, a wiredor wireless connection, or others, and store a logic, such asprojections, depressions, holes, modules, objects, programs, apps,firmware, microcode, or other forms of instruction, for execution viathe processor 204. For example, the logic can be programmed or input viaa (1) a manufacturer of the system 200A, (2) a distributor of the system200A, (3) a retailer of the system 200A, (4) a wholesaler of the system200A, or (5) a user of the system 200A, such as a medical serviceprovider, a patient, or others. For example, a pharmacist can receivethe system 200A programmed for use with a specific medical condition,disease, or disorder or a specific dosage or a specific patient or thepharmacist can receive the system 200A without being programmed for usewith a specific medical condition, disease, or disorder or a specificdosage or a specific patient and then the pharmacist can program for usewith a specific medical condition, disease, or disorder or a specificdosage or a specific patient, as disclosed herein. For example, apharmacist or assistant thereof can program, such as over a wired orwireless connection, the logic via a pharmacy electronic terminal, whichcan include an electronic payment device, such as a payment card reader,a mobile phone wallet reader, a currency input device, a bill acceptor,a cash register, or others, or via a point-of-sale (POS) system, whichmay include some, most, or all of the foregoing, and can be positionedin a customer interaction area or a back pharmacy or restrictedpersonnel area, or others. Such programming can include input ormodification of (1) patient identification information, such as personalinformation, biometrics (e.g., fingerprint, retina scan), or others, (2)medical condition, disease, or disorder type, (3) prevention, diagnosis,monitoring, amelioration, or treatment information, such as medicaldevice operation parameters, such as dosages, timing, or others. Forexample, the logic can be executed via the processor 204, such as toauthenticate users, to use or to track use of the medical device 208 forat least one of prevention, diagnosis, monitoring, amelioration, ortreatment, to modify prescription data, to switch the medical device 208between a plurality of modes, to communicate with other devices,accessories, peripherals, to reconfigure, retrofit, or update themedical device 208, or others.

The memory 206 also stores a first content, such as an activation code,a set of prescription data, a set of dosage/frequency of use data, orothers, that is associated with the medical device 208, such as uniquelyor others. For example, the first content can include a content (e.g.,barcode, text, image, sound) that is unique with respect to othersimilar medical devices 208, such as a serial number, a deviceidentifier, a device parameter, or others, or a plurality of medicaldevices listed in a database, as disclosed herein. The first content canbe stored internal or external to the logic stored in the memory 206.The first content can be of any type, such as an alphanumeric, an image,a barcode, a sound, a data structure, a projection, a depression, ahole, or any others. The first content can be formatted in any manner,such as binary, denary, hexadecimal, or others.

The medical device 208 can include one or more sensors, such as, forexample, biosensors, feedback sensors, chemical sensors, opticalsensors, acoustic sensors, vibration sensors, motion sensors, fluidsensors, radiation sensors, temperature sensors, motion sensors,proximity sensors, fluid sensors, or others. The one sensor can be usedto sense and detect various properties, conditions and/orcharacteristics or variations to same or lack thereof. The sensor maygenerate an output, such as one or more outputs, which are communicated,via wire, wirelessly or waveguide, to the medical device 208, a basestation, processor, server, or other logic or computing device. Theoutput may be used as an input to one or more of the foregoing devicesto forecast or avert an imminent onset or predicted upcoming onset of asymptom, episode, condition or disease. For example, as disclosed inU.S. Patent App. Pub. No. 2017/0120052, which is incorporated herein byreference in its entirety for at least these purposes as if copied andpasted herein, as disclosed herein, and for all purposes as if copiedand pasted herein, such as all structures, all functions, and allmethods of manufacture and use, as disclosed therein.

The medical device 208 can be of any type to at least one of prevent,diagnose, monitor, ameliorate, or treat a medical condition, a disease,or a disorder of a patient, such as a mammal, such as a human, whetherinfant, child, adult, or elderly, or others. In the representativeembodiment, medical device 208 is configured for treating conditionsassociated post-operative symptoms following major surgery and/or fortreating patients in critical or intensive care, such as those patient'ssuffering from stroke, transient ischemic attack (TIA), heart, kidney orrespiratory failure, shock, sepsis, severe burns, severe illnesses(e.g., COVID-19) and the like.

In other embodiments, device 208 may be configured for treatingconditions associated with replicating pathogens. The replicatingpathogen may include a bacteria, fungi, protozoa, worm, infectiousprotein (e.g., prion) or a virus, such as an RNA virus. In oneparticular embodiment, the disclosure relates to treating conditionsassociated with viruses. The virus may comprise a virus that contains asensitizing and/or allergenic protein or other molecule that triggers anallergic or inflammatory response in the patient, such as a virus in thecoronaviridae or coronavirus family (e.g., COVID 19). The medical device208 may be further configured for treating patient's suffering fromlong-haul or chronic COVID disease.

The medical device 208 can be configured to output an energy via anenergy source of the medical device 208, such as a mechanical energy viaan actuation source (e.g., actuator) of the medical device 208, anelectrical energy via a current or voltage source (e.g., electrode) ofthe medical device 208, an electromagnetic energy via an impulse source(e.g., generator) of the medical device 208, a thermal energy via aheating (e.g., heating element) or cooling (e.g., ice pack, fan) sourceof the medical device 208, an acoustic energy via an acoustic source(e.g., speaker, transducer) of the medical device 208, or a light energyvia a light source (e.g., bulb, laser beam generator) of the medicaldevice 208. For example, as shown in FIG. 1B, the medical device 208 caninclude a neurostimulator 208B, whether invasive, non-invasive, orhybrid. For example, the neurostimulator 208B can be embodied asdescribed in US Patent Application Publication 2014/0330336 and U.S.Pat. Nos. 8,874,205, 9,037,247, 9,174,066, 9,205,258, 9,375,571, and9,427,581, all of which are herein incorporated by reference for allpurposes as if copied and pasted herein, such as all structures, allfunctions, and all methods of manufacture and use, as disclosed therein.For example, the neurostimulator can modulate central or peripheralnervous systems. For example, the neurostimulator can be enable spinalcord stimulation to provide therapy for intractable pain and refractoryangina; occipital nerve stimulation to provide therapy for occipitalneuralgia and transformed migraine; afferent vagus nerve modulation toprovide therapy for a host of neurological and neuropsychiatricdisorders, such as epilepsy, depression, Parkinson's disease, bulemia,anxiety/obsessive compulsive disorders, Alzheimer's disease, autism, andneurogenic pain; efferent vagus nerve stimulation for rate control inatrial fibrillation, and to provide therapy for congestive heartfailure; gastric nerves or gastric wall stimulation to provide therapyfor obesity; sacral nerve stimulation to provide therapy for urinaryurge incontinence; deep brain stimulation to provide therapy forParkinson's disease, and other neurological and neuropsychiatricdisorders; cavernous nerve stimulation to provide therapy for erectiledysfunction. However, as explained herein, note that the medical device208 can be of any type or modality for at least one of prevention,diagnosis, monitoring, amelioration, or treatment of a medicalcondition, disease, or a disorder of a patient. For example, the medicaldevice 208 can be configured to output a fluid, such as a liquid, asuspension, or a gas. For example, the medical device 208 can beconfigured to output a gel, a powder, or a foam. For example, themedical device 208 can be configured to increase or decrease pressure orprovide physical support, whether internal or external to a patient. Anexample of a device that can be used is a mechanical actuator, vibrationdevice, piezoelectric device, electric motor (e.g., brushed, brushless)or engine (e.g., combustion) or any other force generator, applicator,or output device.

The medical device 208 can operate in a first manner during the firstmode and in a second manner in the second mode, where the first manneris different from or identical to the second manner, such as in anamount of operation, in an intensity of operation, in a duration ofoperation, in a modality of operation, in an energy use of operation, orothers. For example, when the processor 204 switches the medical device208 from the first mode (e.g., a deactivated mode) to the second mode(e.g., an activate mode), then such switching can activate the medicaldevice 208 for a specific time period or a number of diagnosis ortreatment doses or other parameters or vice versa. For example, theamount of operation includes a number of individual doses of at leastone of diagnosis or treatment doses, such as less than or more than 3doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses,15 doses, 20 doses, 25 doses, 30 doses, 40 doses, 45 doses, 50 doses, 60doses, 65 doses, 70 doses, 75 doses, 80 doses, 85 doses, 90 doses, 95doses, 100 doses, 200 doses, 300 doses, 400 doses, 500 doses, 600 doses,700 doses, 800 doses, 900 doses, 1000 doses, or any other amount ofdoses from 1 to 1000 or greater, or others, whether a dose is based on asingle use or a set of uses within a predefined time period (e.g.,milliseconds, seconds, minutes, hours, days, weeks, months, years). Assuch, the medical device 208 can be adjusted where the first mode andthe second mode can be equal or unequal in amount of doses.

Similarly, the intensity of operation includes a degree or type ofintensity with which the medical device 208 at least one of prevents,diagnoses, monitors, ameliorates, or treats the medical condition,disease, or the disorder in the patient. For example, the first mode canbe associated with a first prevention, diagnosis, monitoring,amelioration, or treatment signal/energy output and the second mode canbe associated with a second prevention, diagnosis, monitoring,amelioration, or treatment signal/energy output, wherein the firstsignal/energy output is identical to or differs from the secondsignal/energy output in various parameters, such as a content, a format,an amplitude, a frequency, a time period, or others. As such, themedical device 208 can be adjusted to more intensely or less intenselyprevent, diagnose, monitor, ameliorate, or treat based on switchingbetween the first mode and the second mode. Likewise, the duration ofoperation includes a number of defined time periods during which themedical device can at least one of prevent, diagnose, monitor,ameliorate, or treat, such as a number of seconds, minutes, hours, days,weeks, months, or others, whether dependent on usage or independent ofusage. As such, the medical device 208 can be adjusted to a least one ofprevent, diagnose, monitor, ameliorate, or treat between a first definedtime period and a second defined time period.

The input device 210 is configured to obtain, such as via reading,copying, or others, a second content from a storage medium, such as amagnetic card, a radio frequency identification (RFID) card, a chipcard, a barcode, a Quick Response (QR) code, or others, such that theprocessor 204 switches the medical device 208 between the first mode andthe second mode based on the first content corresponding to the secondcontent, such as logically or others, or vice versa. The second content,such as an activation code, a set of prescription data, a set ofdosage/frequency of use data, or others, can be associated with themedical device 208, such as uniquely or others, with a specific mode ofoperation, such as for preventing, diagnosing, monitoring, ameliorating,or treating a specific medical condition, disease, or disorder, or witha particular user, such as based on a user identifier, such as apersonal identification number (PIN), a biometric, or others. Note thatthe particular user can be associated with the medical device 208, suchas via a primary key of a relational database, as disclosed herein. Forexample, the primary key can be the PIN or another set of data such thatthe second content is unique to the particular user. In someembodiments, where the medical device 208 is shared among a plurality ofusers, the second content can be unique to one of the users, yet accesscontrol or authentication between the users can be controlled viaanother layer or form of identification, such as passwords, biometrics,or others, such as when the system 200A includes a user input devicecoupled to the processor 204. For example, the user input device caninclude a keyboard or dial, whether physical, virtual (e.g., display),or haptic (e.g., display), a biometric reader, a fob or tag, a barcode,or others.

The second content can be of any of type, whether identical to ordifferent from the first content, such as an alphanumeric, an image, abarcode, a sound, a data structure, a projection, a depression, a hole,or any others. The second content can be formatted in any manner,whether identical to or different from the first content, such asbinary, denary, hexadecimal, or others.

The input device 210 can be of any modality or type, such as a camera, amicrophone, a sensor, a card reader, a signal receiver, or others. Forexample, as shown in FIG. 16B, the input device 210 includes a reader210B, such as a reader terminal, that is configured to read the secondcontent from the storage medium, such as a card, a display, aninterface, a chip, a memory dongle, a paper, or others, whether thestorage medium is in or out of a line-of-sight of the reader 210B. Forexample, when the storage medium is a card, which can include paper,cardboard, plastic, rubber, metal, wood, or others, and the reader 210Bis a card reader, then the card can be embedded with at least one of abarcode, a magnetic strip, a computer chip, or another storage mediumand the card reader can read the at least one of the barcode, themagnetic strip, the computer chip, or another storage medium. Forexample, the memory dongle can include a Universal Serial Bus (USB)dongle, a CompactFlash (CF) card, Secure Digital (SD) card, aMultiMediaCard (MMC) card. Therefore, the card can be a dumb card, asmart card, a memory card, a Wiegand card, a proximity card, or others,whether contact or contactless. Correspondingly, the reader 210B can bea smart card reader, a memory card reader, a Wiegand card reader, amagnetic stripe reader, a proximity reader, or others, whether thereader 210B is a non-intelligent reader, a semi-intelligent reader, oran intelligent reader. The input device 210 can be distinct from themedical device 208 or be a component of the medical device 208. Thememory 206 can include the storage medium (e.g., removable memory chip)or vice versa. The memory 206 can exclude the storage medium or viceversa.

Similarly, as shown in FIG. 16C, the input device 210 includes atransceiver 210C, which includes a receiver, that is configured toreceive, whether over a wired, wireless, or waveguide connection, thesecond content from the storage medium, such a card, a phone, a tablet,a laptop, a wearable, or others, such via a radio technique, an opticaltechnique, an acoustic technique, or others, whether the storage mediumis in or out of a line-of-sight of the transceiver 210C. For example,the radio technique can include a RFID interrogation, a Wi-Ficommunication, a Bluetooth communication, or other radio communicationformats, which can be encrypted or unencrypted. For example, the opticaltechnique can include a laser beam, an infrared beam, a Li-Ficonnection, or others. Note that the transceiver can include atransmitter or a receiver.

The input device 210 can obtain the second content from the storagemedium in various ways. For example, the input device 210 can obtain thesecond content electronically, optically, electromagnetically,mechanically, or others, whether the storage medium is in or out of aline-of-sight of the input device 210. For example, when the inputdevice 210 is the reader 210B, then the input device 210 can read thesecond content from the storage medium based on at least one of abarcode of the storage medium (optically), a QR code of the storagemedium (optically), a magnetic material of the storage medium(electromagnetically), a chip of the storage medium(electromagnetically), an integrated circuit of the storage medium(electronically), a non-volatile memory of the storage medium(electronically), a punched hole of the storage medium (mechanically), atactile surface of the storage medium (mechanically), or others.Likewise, when the input device 210 is the transceiver 210C, then theinput device 210 can read the second content from the storage medium viaan RFID technique, such as via interrogation, whether the storage mediumis passive or active. Note that in some embodiments, the input device210 includes the reader 210B and the transceiver 210C.

The first content can correspond to the second content in various ways,such as logically, such as via a Boolean logic, or others. For example,the first content can match the second content in content, format,logic, parameters, encryption, or others. For example, the first contentcan be equal to the second content, whether in format or value.Similarly, the first content can be unequal to the second content,whether in format or value. Likewise, the first content can logicallymap to the second content, such as via a logical symmetry where thefirst content is same as the second content or where the first contentis different from the second, but related in a relatively quickcomputational way. For example, such correspondence can be determinedbased on or via hashing the first content or the second content. In someembodiments, processor 204 or the input device 210 can convert the firstcontent or the second content before determining whether the firstcontent corresponds to the second content. For example, such conversioncan involve a format or a content of the first content or the secondcontent.

When the first content does not correspond to the second content, suchas the first content does not match the second content in value andformat or others, as described above, then the medical device 208 is notswitched from the first mode, such as a deactivated mode, to the secondmode, such as an activated mode. In some embodiments, when the firstcontent does not correspond to the second content, then the medicaldevice 208 is switched from the first mode to the second mode, but thesecond mode is as or less operational than the first mode. For example,the second mode is a default mode of operation, a minimal mode ofoperation, a demo mode of operation, a disabled mode of operation, akiosk mode of operation, or others.

In some embodiments, the system 100 includes an output device, such as asignal transmitter, a light, sound, or vibration source, an actuator, adata writer, or others, coupled to the processor 204, whether over awired, wireless, or waveguide connection, where the processor 204 isconfigured to instruct the output device to interface with the storagemedium in response to the input device 210 reading the second content.For example, the output device can include a transmitter and theprocessor 204 can instruct the transmitter to send a signal to thestorage medium such that the storage medium can receive and process thesignal, which may involve acting based on such processing. For example,such action can allow deactivating the storage medium based on or afterthe medical device 208 is switched from the first mode, such as adeactivated mode, to the second mode, such as an activated mode. Forexample, the processor 204 can request the output device to interfacewith the storage medium such that the storage medium is locked fromfurther reading, when the storage medium is enabled for such locking.Similarly, the processor 204 can request the output device to interfacewith the storage medium such that the second content on the storagemedium is rendered unusable, when the storage medium is enabled for suchdata modification rights. Likewise, the processor 204 can request theoutput device to interface with the storage medium such that the secondcontent on the storage medium is erased from the storage medium, whethertemporarily or permanently, when the storage medium is enabled for suchdata modification rights. Also, the processor 204 can request the outputdevice to interface with the storage medium such that the storage mediumis reformatted, when the storage medium is enabled for such datamodification rights. Additionally, the processor 204 can request theoutput device to interface with the storage medium such that the storagemedium is modified from a first state to a second state, when thestorage medium is enabled for such state modification rights, and wherethe first state is before the input device 210 obtains the secondcontent from the storage medium, and where the second state is after theinput device 210 obtains the second content from the storage medium.Note that such interfacing can include electronically or physicallymodifying the storage medium or a content or data format thereon. Notethat the first state and the second state can differ from each other invarious ways (e.g., more or less functionality, more or less energy use,more or less data reading or modification or deletion or reformattingrights). As such, the output device can be useful to lock or wipe thestorage medium once the input device 210 reads the second content fromthe storage medium.

When the system 200A is used to at least one of prevent, diagnose,monitor, ameliorate, or treat the medical condition, disease, or thedisorder of the patient, the processor 204 tracks such use and can takean action when a predetermined threshold is satisfied or not satisfied,such as via the logic stored via the memory 206. For example, the logictracks a use of the medical device 208 and when a number of uses, asprogrammed in advance, satisfies or does not satisfy the predeterminedthreshold, then the processor 204 can take an action, such as switch themedical device 208 between the first mode, such as an activated mode,and the second mode, such as a deactivated mode, or vice versa. Notethat the logic has access to or can modify the predetermined threshold.Further, note that the predetermined threshold can be based on a numberof single uses within a predefined time period (e.g., within a day, aweek, a month, a year) or a number of single uses regardless of any timelimit. For example, the action can include activating the medical device208, deactivating the medical device 208, creating, modifying, ordeleting a prevention, diagnosis, monitoring, amelioration, or treatmentparameter of the medical device 208, as stored via the medical device208 or the memory 206, creating, modifying, or deleting a set oftreatment instructions of the medical device 208, as stored via themedical device 208 or the memory 206, or others.

In one mode of operation, a user of the system 200A positions thestorage medium in proximity thereof, such as within about ten feet orless. The input device 210 interfaces with the storage medium such thatthe processor 204 switches the medical device 208 between the first modeand the second mode. If the first mode was a deactivated mode and thesecond mode was an activated mode, then the user can use the system 200Ato prevent, diagnose, monitor, ameliorate, or treat the medicalcondition, disease, or the disorder of the user or another. For example,the input device 210 can read the second content from the storage mediumand pass the second content to the processor 204. In response, theprocessor 204 can confirm that the first content, which is uniquelyassociated with the medical device 208, matches the second card, such asvia value and format. Upon such confirmation, the processor 204 switchesthe medical device 208 from the first mode to the second mode.

FIG. 17 shows a schematic diagram of an embodiment of a network diagramfor initially provisioning and refilling a system containing a medicaldevice according to this disclosure. FIG. 18 shows a flowchart of anembodiment of a method for initially provisioning a system containing amedical device according to this disclosure. In particular, a system 500includes a network 502, a pharmacy client 504, an input device 506, amedical device 508, a server 510, and a doctor client 512. The network502 is in communication, whether over a wireless, wired, or waveguideconnection, with the pharmacy client 504, the server 510, and the doctorclient 512. The pharmacy client 504 is in communication, whether over awireless, wired, or waveguide connection, with the input device 506 andthe network 502.

The network 502 includes a plurality of nodes that allow for sharing ofresources or information. The network 502 can be wired or wireless. Forexample, the network 502 can be a local area network (LAN), a wide areanetwork (WAN), a cellular network, a satellite network, or others.

Each of the pharmacy client 504 and the doctor client 512 is aworkstation that runs an operating system, such as MacOS®, Windows®, orothers, and an application, such as an administrator application, on theoperating system. The workstation can include and/or be coupled to,whether directly and/or indirectly, an input device, such as a mouse, akeyboard, a camera, whether forward-facing and/or back-facing, anaccelerometer, a touchscreen, a biometric reader, a clicker, amicrophone, a barcode or QR code reader, or any other suitable inputdevice. The workstation can include and/or be coupled to, whetherdirectly and/or indirectly, an output device, such as a display, aspeaker, a headphone, a printer, or any other suitable output device. Insome embodiments, the input device and the output device can be embodiedin one unit, such as a touch-enabled display, which can be haptic. Assuch, the application presents a graphical user interface (GUI)configured to interact with a user to perform various functionality, asdisclosed herein. In some embodiments, the application on the pharmacyclient 504 can operate in an administrator mode and a kiosk mode, suchas an agent mode or others, where the administrator mode has more orhigher access privileges than the kiosk mode, where the kiosk mode isused for programming the medical device 508 or coupling the medicaldevice 508 to the storage medium, as disclosed herein. Note that theapplication on the pharmacy client 204 can control access between theadministrator mode and the kiosk mode via user identifiers, passwords,biometrics, or others. Further, note that at least one of the pharmacyclient 204 or the doctor client 212 can be a non-workstation computer aswell, such as a smartphone, a tablet, a laptop, a wearable, an eyewearunit, or others.

The server 510 runs an operating system, such as MacOS®, Windows®, orothers, and an application, such as a prescription managementapplication, on the operating system. In some embodiments, the server510 hosts or has access to a database, such as a relational database, anin-memory database, a graphical database, a NoSQL database, or others.For example, the database can include a plurality of records, where eachof the records contains a plurality of fields associated with aplurality of categories, such as patient identifier, patient contactinformation, patient medical record, prescription name, prescriptiondosage, and others. Note that the database can include or be coupled toan electronic medical records (EMR) database, whether local or remotethereto, whether using a same or different schema (e.g., star, tree).The server 510 can include and/or be coupled to, whether directly and/orindirectly, an input device, such as a mouse, a keyboard, a camera,whether forward-facing and/or back-facing, an accelerometer, atouchscreen, a biometric reader, a clicker, a microphone, or any othersuitable input device. The server 510 can include and/or be coupled to,whether directly and/or indirectly, an output device, such as a display,a speaker, a headphone, a printer, or any other suitable output device.In some embodiments, the input device and the output device can beembodied in one unit, such as a touch-enabled display, which can behaptic.

The input device 506 is coupled to the pharmacy client 504, whether overin a wired, wireless, or waveguide connection, and can include a camera,a microphone, a keyboard, whether physical or virtual, a reader, orothers. The input device 504 can be battery energized or energized viathe pharmacy client 504.

The medical device 208, such as the system 200A, the medical device 208,or others, comprises a device identifier, such as the first content, asdisclosed herein, whether internally, such as via the memory 206 orothers, or externally, such as on the medical device 208 itself, on atag coupled to the medical device 208, such as via adhering, fastening,mating, or others, or on a tag coupled to or depicted or printed on apackage containing the medical device 208.

In one mode of operation, as shown in FIG. 18 , in order to initiallyprovision the medical device 508, the doctor client 512 sends a set ofprescription data to the server 510 over the network 502. As per block522, the pharmacy client 504 retrieves (e.g., reads, copies) the set ofprescription data from the server 510 over the network 502, such as viaa patient identifier associated with a record of the database accessibleto the server 510. Upon retrieval, the pharmacy client 504 displays theset of prescription data thereon.

As per block 520, a user of the pharmacy client 504 uses the inputdevice 506 to obtain the device identifier from the medical device 508.For example, when the device identifier, such as the first content, isinternal to the medical device 508, then the input device 506 caninterface with the medical device 508, whether over a wired, wireless,or waveguide connection, and obtain the device identifier, such as viaan RFID interrogation or others. Likewise, when the device identifier isexternal to the medical device 508, then the input device 206 obtainsthe device identifier via reading the device identifier, such as viabarcode or QR code scanning or others. Note that the block 520 can occurbefore, during, or after the block 522. As such, once the pharmacyclient 504 has the device identifier and the set of prescription data,as per block 524, the pharmacy client 504 associates the deviceidentifier and the set of prescription data, whether locally or on theserver 510, such as via relating the device identifier and the set ofprescription data in the database, such as via a primary key or others.Therefore, as per block 526, an action can be taken with the medicaldevice 508. For example, the action can be via the pharmacy client 510prompting a message that the medical device 508 is associated with theset of prescription data, generating a sound alert, modifying a datastructure, or others. Similarly, the action can include packaging orrepackaging the medical device 508, shipping the medical device 508,handing over the medical device 508 to a patient, or others.

FIG. 19 shows a flowchart of an embodiment of a method for refilling asystem containing a medical device according to this disclosure. Inparticular, in order to refill the medical device 508, the doctor client512 sends a set of prescription data to the server 510 over the network502. As per block 532, the pharmacy client 504 retrieves (e.g., reads,copies) the set of prescription data from the server 510 over thenetwork 502, such as via a patient identifier associated with a recordof the database accessible to the server 510. Upon retrieval, thepharmacy client 504 displays the set of prescription data thereon.

As per block 530, a user of the pharmacy client 504 uses the inputdevice 506 to obtain the device identifier from the medical device 508.For example, when the device identifier, such as the first content, isinternal to the medical device 508, then the input device 506 caninterface with the medical device 508, whether over a wired, wireless,or waveguide connection, and obtain the device identifier, such as viaan RFID interrogation or others. Likewise, when the device identifier isexternal to the medical device 508, then the input device 506 obtainsthe device identifier via reading the device identifier, such as viabarcode or QR code scanning or others. Note that the block 530 can occurbefore, during, or after the block 532.

As such, once the pharmacy client 504 has the device identifier and theset of prescription data, as per block 534, the pharmacy client 504 canbe used to program or reprogram a storage medium, such as an RFID cardor others, based on the set of prescription data, via an output device,such as a signal transmitter, a light, sound, or vibration source, anactuator, a data writer, or others, coupled to the pharmacy client 504,whether over a wired, wireless, or waveguide connection. For example,such programming can be via an RFID interrogation or other technologies.For example, such programming can involve using the pharmacy client 504to program the storage medium to match the device identifier that isuniquely associated with the medical device 508. For example, thepharmacy client 504 can instruct the output device to interface with thestorage medium, such as via adding, modifying, or deleting content orformat to or from the storage medium such that the storage medium storesthe set of prescription data or a logic containing a set of instructionsto operate the medical device 508 according to the set of prescriptiondata. Note that this logic can be included in the set of prescriptiondata or generated via the server 510 or the pharmacy client 504 based onthe set of prescription data. In some embodiments, the medical device508 generates this logic based on the set of prescription data asobtained from the storage medium. Therefore, the storage medium can bepositioned in proximity (e.g., within about 10 feet or less) of thesystem 200A to be read via the input device 510 such that the processor504 can switch the medical device 508 between the first mode and thesecond mode. Note that for recordkeeping purposes, the pharmacy client504 can communicate (e.g., email, texting, social networking,over-the-top) a message informative of such programming to the server510 over the network 502, such as for writing into the record of thepatient in the database. For example, the pharmacy client 504 associatesthe device identifier and the set of prescription data, whether locallyor on the server 510, such as via relating the device identifier and theset of prescription data in the database, such as via a primary key orothers.

Consequently, as per block 536, the storage medium, as programmed, canbe provided to the patient, such as via handing over to the patient,packaging/shipping to the patient, or communicating to the patient, suchas via email, text, social networking, over-the-top messaging, orothers. As such, a POS terminal, such as the pharmacy client 504, can beused to (1) obtain a device identifier from the medical device 508, (2)retrieve a set of prescription data from the server 510, where thedevice identifier is uniquely associated with the medical device 508,and (3) program, such as via encoding or others, a storage medium, suchas an RFID card or others, based on the device identifier and the set ofprescription data such that the medical device 508 can be switched froma first mode, such as a deactivated mode, to a second mode, such as anactivated mode, or load a set of new therapy dose data, based on thestorage medium being in proximity of the medical device 508.

In some embodiments, the output device can include a transmitter (e.g.,wired, wireless, waveguide) and the pharmacy client 504 can instruct thetransmitter to send (e.g., wired, wireless, waveguide) a signal to thestorage medium such that the storage medium can receive and process thesignal, which may involve acting based on such processing. For example,the pharmacy client 504 can request the output device to interface withthe storage medium such that the storage medium is locked from furtherreading or writing or modifying or deleting, whether in data or format,when the storage medium is enabled for such locking. Similarly, thepharmacy client 504 can request the output device to interface with thestorage medium such that the second content on the storage medium isrendered unusable, when the storage medium is enabled for such datamodification rights. Likewise, the pharmacy client 504 can request theoutput device to interface with the storage medium such that the secondcontent on the storage medium is erased from the storage medium, whethertemporarily or permanently, when the storage medium is enabled for suchdata modification rights. Also, the pharmacy client 504 can request theoutput device to interface with the storage medium such that the storagemedium is reformatted, when the storage medium is enabled for such datamodification rights. Note that such interfacing can includeelectronically or physically modifying the storage medium or a contentor data format thereon or an encryption thereon.

FIG. 20 shows a flowchart of an embodiment of a method for using asystem containing a medical device according to this disclosure. Inparticular, as per block 540, a storage medium, such as an RFID card orothers, is positioned in proximity of the input device 510, such as anRFID reader, such that the input device 510 can read a content of thestorage medium. For example, the content can include an activation codeand a set of prescription data, such as a therapy dosage or others. Forexample, such reading can occur at a patient location such as at home,at work, or others, at a pharmacy location, such as at a retail kiosk orothers, at a manufacturer location, such as at a warehouse or others, orothers. As per block 544, responsive to such reading, the processor 504switches the medical device 508 from a first mode, such as a deactivatedmode, to a second mode, such as an activated mode. In some embodiments,the processor 504 instructs the output device of the system 200A tocommunicate with the storage medium in order to deactivate the storagemedium, as disclosed herein, such as via deleting the content from thestorage medium, reformatting the card, or others. As per block 544, theprocessor 504 tracks usage of the medical device 508 in order to becompliant with the content of the storage medium as read by the inputdevice 510. For example, if the content mandates 1 use during 24 hoursfor 1 week, then the processor 504 track time, days, and usage per dayor another time period (e.g., minutes, hours). As per block 544, if theprocessor 504 determines that the usage of the medical device hasreached a predetermined threshold, as per the content read from thestorage medium, then the processor 504 switches the medical device 508from the second mode (the activated mode) to the first mode (thedeactivated mode), otherwise the processor 504 allows the usage of themedical device 508. For example, if the content mandates 1 use during 24hours for 1 week, then the processor 504 switches the medical device 508from the second mode to the first mode when 1 week from first use of themedical device 508 passed.

A more complete description of systems and methods of using medicaldevice 208 can be found in commonly-assigned, co-pending U.S. patentapplication Ser. No. 16/229,299, filed Dec. 21, 2018, the completedisclosure of which is incorporated herein by reference for allpurposes.

Various corresponding structures, materials, acts, and equivalents ofall means or step plus function elements in various claims below areintended to include any structure, material, or act for performing thefunction in combination with other claimed elements as specificallyclaimed. Various embodiments were chosen and described in order to bestexplain various principles of this disclosure and various practicalapplications thereof, and to enable others of ordinary skill in apertinent art to understand this disclosure for various embodiments withvarious modifications as are suited to a particular use contemplated.

Various diagrams depicted herein are illustrative. There can be manyvariations to such diagrams or steps (or operations) described thereinwithout departing from various spirits of this disclosure. For instance,various steps can be performed in a differing order or steps can beadded, deleted or modified. All of these variations are considered apart of this disclosure. People skilled in an art to which thisdisclosure relates, both now and in future, can make variousimprovements and enhancements which fall within various scopes ofvarious claims which follow.

The invention claimed is:
 1. A method for treating post-operativesymptoms in a patient, the method comprising: attaching a patch to theouter skin surface of a neck of the patient, wherein the patch comprisesone or more electrodes; generating an electrical impulse with a device;wirelessly transmitting the electrical impulse from the device to theone or more electrodes; the electrical impulse transcutaneously from theone or more electrodes through the outer skin surface of the patient toa vagus nerve in the patient according to a stimulation protocol thatincludes at least two doses administered each day for a plurality ofdays, wherein the doses each have a duration of about sixty seconds toabout 5 minutes; and wherein the electrical impulse is sufficient tomodify the vagus nerve such that symptoms of intraperitoneal orretroperitoneal inflammation are reduced.
 2. The method of claim 1,wherein the electrical impulse comprises pulses having a frequency ofabout 1 kHz to about 20 kHz.
 3. The method of claim 2, wherein theelectrical impulse comprises bursts of pulses, with each burst having afrequency of about 1 to about 100 bursts per second and each pulse has aduration of about 50 to about 1000 microseconds in duration.
 4. Themethod of claim 3, wherein the bursts each comprise about 2 to 20 pulsesand the bursts are separated by an inter-burst period that compriseszero pulses.
 5. The method of claim 1, wherein at least one of the dosesis administered to the patient prior to a surgery.
 6. The method ofclaim 5, wherein at least of the doses is administered to the patientafter the surgery.
 7. The method of claim 1, wherein the doses areseparated by a time frame of about 1 hour to about 12 hours.
 8. Themethod of claim 1, wherein the stimulation protocol comprises 2 to 12treatments/day.
 9. The method of claim 1, wherein the electrical impulseis sufficient to inhibit a release of a pro-inflammatory cytokine. 10.The method of claim 1, wherein the electrical impulse is sufficient toreduce post-operative pain.